Transcapillary Escape Rate Of Albumin Research Articles

Albumin and fibrinogen synthesis rates in advanced chronic liver disease.

Synthesis of plasma proteins is an important function of the liver that has sparsely been investigated by modern techniques in patients with advanced chronic liver disease (CLD). Twenty-eight well-characterized patients with CLD under evaluation for liver transplantation were included. Albumin and fibrinogen synthesis rates were measured by the flooding dose technique using stable isotope labelled phenylalanine. Transcapillary escape rate of albumin and plasma volume were assessed by radio-iodinated human serum albumin. The absolute albumin synthesis rates were low (65 mg/kg/day, range 32-203), and associated with impaired liver function, as reflected by the risk-scores Child-Pugh (p = 0.025) and Model for End-stage Liver Disease rs = -0.62, p=0.0005. The fibrinogen synthesis rate (12.8 mg/kg/day, range 2.4-52.9) was also negatively associated with liver function. The synthesis rates of albumin and fibrinogen were positively correlated. Plasma volume was high (51 ± 9 mL/kg body weight), which contributed to an almost normal intravascular albumin mass despite low plasma concentration. Autoimmune inflammatory etiologies to CLD were associated with higher fibrinogen synthesis. De novo synthesis rates of albumin and fibrinogen in advanced chronic liver failure were negatively correlated to prognostic scores of liver disease. Albumin synthesis rate was low and associated with both liver failure and autoimmune inflammation, while fibrinogen synthesis was often normal and positively associated with chronic inflammation. This is different from acute inflammatory states in which both albumin and fibrinogen synthesis rates are high.

Transcapillary escape rate of 125I-albumin in relation to timing of blood sampling: the need for standardization

BackgroundIncreased vascular permeability is an early sign of vascular damage and can be measured with the transcapillary escape rate of albumin (TERalb). Although TERalb has a multi-exponential kinetic model, most published TERalb data are based on mono-exponential kinetic models with variation in blood sampling schemes. Aim of this posthoc study was to evaluate the influence of variation in blood sampling schemes and the impact of mono- or bi-exponential analyses on the calculation of TERalb. Study participants were part of a cross-over intervention study protocol, investigating effects of sodium loading on blood pressure, endothelial surface layer and microcirculation. Multiple blood samples were drawn between 3 and 60 min after injection of radioactive iodide labeled human serum albumin (rHSA).ResultsIn total 27 male participants with 54 measurements were included. For all participants the maximum serum radioactivity was reached within 20 min, while 85% of the participants had their maximum serum activity within 10 min. The TERalb calculated with the subsequently chosen T20–60 min reference scheme (6.19 ± 0.49%/h) was significantly lower compared to the TERalb of the T3–60 min, T5–60 min, and Tmax – 60 min schemes. There was no significant difference between the T20–60 min reference scheme and the T10–60 min and T15–60 min schemes. Bi-exponential kinetic modeling did not result in significant different observations compared to the mono-exponential kinetic analysis.ConclusionsAs there is variation in the timing of the maximum serum radioactivity of rHSA, blood sampling schemes starting before 10 min after administration of rHSA will result in a significant overestimation of TERalb. In addition, variation in kinetic modeling did not result in significant changes in TERalb. Therefore, we emphasize the need to standardize TERalb and for practical and logistical reasons advocate the use of a mono-exponential model with blood sampling starting 20 min after rHSA administration.

Albumin disposition in critically Ill patients.

The purpose of this critical narrative review is to analyse studies evaluating the disposition of albumin in critically ill patients and to compare the findings to studies involving healthy subjects and less severely ill patients. PubMed and EMBASE were reviewed for prospective studies involving the disposition of radiolabelled albumin. Studies of normal volunteers, patients undergoing surgical procedures and critically ill patients indicate a relationship between increasing disease acuity or severity and increasing transcapillary escape of albumin. In the only study that directly compared the disposition of radiolabelled albumin in healthy subjects and patients with septic shock, the transcapillary escape rate of albumin was more than twice as rapid in the patients with shock. Limited studies suggest that increasing disease severity increases transcapillary escape of albumin. Only one study compared the disposition of radiolabelled albumin in healthy subjects and critically ill patients. More studies are needed in subsets of critically ill patients.

A study of predictive value of microalbuminuria in early outcome of non-diabetic patients of acute myocardial infarction

Background: Excretion of albumin in urine, in the range of 30-300 mg/day is called microalbuminuria, which cannot be detected by routine urine tests. The presence of increased UAE (Urinary albumin excretion) signals an increase in the transcapillary escape rate of albumin and is therefore a marker of micro vascular disease. Thus, microalbuminuria is an early response to myocardial infarction.Methods: A prospective study of 50 patients of acute myocardial infarction was carried out to find out the sensitivity and the specificity of microalbuminuria in non-diabetic patients of acute STEMI; to verify the association between the level of microalbuminuria and the area of infarcts; and to establish the correlation of microalbuminuria with cardiac biomarkers.Results: Microalbuminuria test was positive in 92% patients in the study group and 20% subjects in the control group. The sensitivity of microalbuminuria in our study is 92% and the specificity is 80%. The level of Microalbuminuria does not statistically correlate with areas of myocardial infarction.Conclusions: Microalbuminuria is a non-specific yet highly sensitive marker of myocardial infarction and it can be used as an additional biochemical parameter in non-diabetic patients with acute myocardial infarction. Prognostic marker value of microalbuminuria appears unproved.

The importance of albumin infusion rate for plasma volume expansion following major abdominal surgery - AIR: study protocol for a randomised controlled trial.

BackgroundAdministration of fluids to restore normovolaemia is one of the most common therapeutic interventions performed peri-operatively and in the critically ill, but no study has evaluated the importance of infusion rate for the plasma volume-expanding effect of a resuscitation fluid. The present study is designed to test the hypothesis that a slow infusion of resuscitation fluid results in better plasma volume expansion than a rapid infusion.Methods/designThe study is a single-centre, assessor-blinded, parallel-group, randomised prospective study. Patients over 40 years of age admitted to the post-operative care unit after a Whipple procedure or major gynaecological surgery and presenting with signs of hypovolaemia are eligible for inclusion. Patients are randomised in a 1:1 fashion with no stratification to either rapid (30 minutes) or slow (180 minutes) infusion of 5% albumin at a dose of 10 ml/kg ideal body weight. Plasma volume is measured using 125I human serum albumin at baseline (prior to albumin infusion) as well as at 30 minutes and 180 minutes after infusion start. The primary endpoint is change in plasma volume from baseline to 180 minutes after the start of 5% albumin infusion. Secondary endpoints include the integral of plasma volume over time from baseline to 180 minutes after the start of the infusion and transcapillary escape rate of albumin (%/h) from 180 minutes to 240 minutes after the start of albumin infusion. In addition, diuresis, change in central venous oxygen saturation, lactate and blood pressure will be evaluated. A total of 70 patients will be included in the study, and the study has 80% power to detect a difference of 4 ml/kg in plasma volume expansion between the two groups.DiscussionThe present study is the first clinical investigation of the importance of infusion rate for the plasma volume-expanding effect of a resuscitation fluid.Trial registrationEudraCT identifier: 2013-004446-42. Registration date: 20 December 2013.ClinicalTrials.gov identifier: NCT02728921. Registration date: 31 March 2016.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-016-1714-5) contains supplementary material, which is available to authorized users.

Simultaneous assessment of the synthesis rate and transcapillary escape rate of albumin in inflammation and surgery.

BackgroundBetter knowledge of albumin kinetics is needed to define the indications for albumin use in clinical practice. This study involved two approaches: the synthesis rate and transcapillary escape rate of albumin were measured simultaneously at different levels of plasma albumin concentration in relation to acute inflammation and surgery; and two different tracers were compared to determine plasma volume and the transcapillary escape rate.MethodsHealthy volunteers (n = 10), patients with acute inflammatory abdominal disease (n = 10), and patients undergoing elective pancreatic resection (n = 10) were studied. The albumin synthesis rate was measured by the incorporation of deuterium-labeled phenylalanine. Plasma volume and the transcapillary escape rate were assessed using 123I-labeled and 125I-labeled albumin.ResultsA 50 % elevated de-novo albumin synthesis rate was seen in patients with acute inflammation and marked hypoalbuminemia, while patients with marginal hypoalbuminemia before the start of surgery had a normal albumin synthesis rate. The transcapillary escape rate was elevated intraoperatively during the reconstructive phase of pancreatic surgery, when plasma albumin was decreased but stable. In acute inflammation with marked hypoalbuminemia, the transcapillary escape rate was no different from normal. 123I-labeled and 125I-labeled albumin were found exchangeable for plasma volume determinations, but could be used only in groups of patients for the transcapillary escape rate.ConclusionsThis observational study illustrates the limited information contained in albumin plasma concentrations to reflect albumin kinetics. On the contrary, single measurements of the synthesis rate and/or transcapillary escape rate of albumin obviously cannot explain the plasma level of albumin or the changes seen in plasma albumin concentration.Trial registration www.clinicaltrials.gov, study number NCT01686776. Registered 13 September 2012.

Albumin Turnover in Peritoneal and Hemodialysis.

The turnover of albumin is increased in both peritoneal dialysis (PD) and hemodialysis (HD) due to increased external losses, normally leading to compensatory increases in the hepatic albumin synthesis. The normal rate of albumin synthesis is on the order of 12 g/day corresponding to an equally large albumin fractional catabolic rate of ~4% daily. Most albumin catabolism is assumed to occur in the endothelium, but there is also renal and hepatic catabolism and leakage into the gastrointestinal tract. In PD the daily losses are on the order of 5 g/day. There are also external albumin losses in HD, particularly when high-performance membranes are used, the losses per session ranging between 1 and 8 g (or more). The dialytic albumin losses cannot be detected by assessing the transcapillary escape rate of albumin from the plasma compartment to the interstitium. In PD, tracer albumin that has been injected into the peritoneal fluid is absorbed to the tissues surrounding the peritoneal cavity without much edema formation, due to the process of "volume recirculation". A small fraction of the dialysate albumin tracer (0.2-0.3 ml/minute) is directly reabsorbed to the plasma via the lymphatics. A significant portion of dialysis patients are affected by chronic inflammation, such as in the malnutrition inflammation and atherosclerosis syndrome, which is also associated with cardiovascular mortality and fluid overload. These patients usually have a reduced ability to compensate for external losses of albumin, which may result in hypoalbuminemia. Reduced plasma albumin levels in dialysis patients may thus be regarded as a sign of chronic inflammation rather than reflecting malnutrition.

Dicarbonyl stress in clinical obesity.

The glyoxalase system in the cytoplasm of cells provides the primary defence against glycation by methylglyoxal catalysing its metabolism to D-lactate. Methylglyoxal is the precursor of the major quantitative advanced glycation endproducts in physiological systems - arginine-derived hydroimidazolones and deoxyguanosine-derived imidazopurinones. Glyoxalase 1 of the glyoxalase system was linked to anthropometric measurements of obesity in human subjects and to body weight in strains of mice. Recent conference reports described increased weight gain on high fat diet-fed mouse with lifelong deficiency of glyoxalase 1 deficiency, compared to wild-type controls, and decreased weight gain in glyoxalase 1-overexpressing transgenic mice, suggesting a functional role of glyoxalase 1 and dicarbonyl stress in obesity. Increased methylglyoxal, dicarbonyl stress, in white adipose tissue and liver may be a mediator of obesity and insulin resistance and thereby a risk factor for development of type 2 diabetes and non-alcoholic fatty liver disease. Increased methylglyoxal formation from glyceroneogenesis on adipose tissue and liver and decreased glyoxalase 1 activity in obesity likely drives dicarbonyl stress in white adipose tissue increasing the dicarbonyl proteome and related dysfunction. The clinical significance will likely emerge from on-going clinical evaluation of inducers of glyoxalase 1 expression in overweight and obese subjects. Increased transcapillary escape rate of albumin and increased total body interstitial fluid volume in obesity likely makes levels of glycation of plasma protein unreliable indicators of glycation status in obesity as there is a shift of albumin dwell time from plasma to interstitial fluid, which decreases overall glycation for a given glycemic exposure.

Reply to Simpson

We appreciate the comments from D. Simpson that, in addition to intensive medical management for a reduction in central venous pressure (CVP) [1], a drop of oncotic pressure due to hypoalbuminaemia in Fontan patients with protein losing enteropathy (PLE) is another explanation for the absence of difference in the CVP between the ‘excellent’ and chronic phase of PLE Fontan patients [2]. In fact, when we looked into our recent data on consecutive 275 stable Fontan patients, including 21 PLE patients, there were no patients with severe hypoalbuminaemia (≤2.5 g/dl) with a CVP of ≥13 mmHg as Bull [3] noted, although there was a significant inverse correlation between the plasma albumin concentration and CVP (r = −0.23, P< 0.0001). Pathophysiological mechanisms of hypoalbuminaemia may be multifactorial in Fontan patients with PLE, although the precise mechanism(s) remains unclear. As demonstrated in patients with heart failure, malnutrition, reduced synthesis of albumin in the congested liver with chronic inflammation and increased transcapillary escape rate of albumin may be additional causes of hypoalbuminaemia [4]. We may have to take those into consideration to care for sicker Fontan patients with long-affected PLE because those patients have some pathophysiological conditions similar to those in heart failure patients, such as chronic inflammation [5]. Thus, once PLE occurred, small CVP decline that we observed due to intensive managements and the hypoalbuminaemia-associated low oncolic pressure may not be sufficient to decrease the high rate of albumin transcapillary escape, leading to sustained hypoalbuminaemia, making the situation more susceptible to oedema [6] and intractable to treat. Those sicker PLE patients require repeated hospitalizations, resulting in poor quality of life after the Fontan operation. Our PLE experience reminds us of an importance of selection criteria for the operation and we have to be aware that a role of Fontan operation is to offer a better quality of life in patients with complex congenital heart disease because of its palliative nature.

Hypoalbuminaemia, systemic albumin leak and endothelial dysfunction in peritoneal dialysis patients

Inflammation, hypoalbuminaemia and peritoneal protein clearance are important predictors of survival in patients treated with peritoneal dialysis (PD). We hypothesized that the common link is abnormal endothelial barrier function. To test this, we explored associations between hypoalbuminaemia, systemic albumin leak and soluble markers of systemic inflammation and endothelial injury. This was a cross-sectional study of 41 prevalent PD patients. Endothelial barrier function was measured as transcapillary escape rate of (125)I albumin [transcapillary escape rate of albumin (TER(alb))]. Seventeen plasma biomarkers including pro-inflammatory cytokines, endothelial biomarkers and metalloproteinases were measured. Hierarchical clustering analysis (HCA) and principal component analysis (PCA) were used to explore the hypothesis. The mean TER(alb) was 13.7 ± 8.9 (%/h), higher than in non-uraemic subjects 8.22 ± 5.8 (%/h). Three patient clusters were defined from HCA according to their biomarker patterns. Cluster 1 was characterized by inflammation, hypoalbuminaemia, overhydration and intermediate TER(alb). Cluster 2 was non-inflamed, preserved muscle mass and more normal TER(alb). Cluster 3 had highest TER(alb), platelet activation, preserved plasma albumin and intermediate high-sensitivity C-reactive protein levels. Two principal components (PCs) were identified from the biomarker matrix, PC1, indicating platelet activation and PC2, pro-inflammatory. TER(alb) was positively related to PC1 but not PC2. Diabetes and ischaemic heart disease were associated with PC1 and PC2, respectively. This exploratory analysis indicates that endothelial barrier function is decreased in PD patients and is associated with diabetic status and markers of platelet activation more than inflammation. In contrast, hypoalbuminaemia is associated more with inflammation and atherosclerotic disease indicating a more complex relationship between systemic endothelial barrier function, inflammation and hypoalbuminaemia which requires further validation.

Effect of sulodexide on endothelial glycocalyx and vascular permeability in patients with type 2 diabetes mellitus

Aims/hypothesisEndothelial glycocalyx perturbation contributes to increased vascular permeability. In the present study we set out to evaluate whether: (1) glycocalyx is perturbed in individuals with type 2 diabetes mellitus, and (2) oral glycocalyx precursor treatment improves glycocalyx properties.MethodsMale participants with type 2 diabetes (n = 10) and controls (n = 10) were evaluated before and after 2 months of sulodexide administration (200 mg/day). The glycocalyx dimension was estimated in two different vascular beds using sidestream dark field imaging and combined fluorescein/indocyanine green angiography for sublingual and retinal vessels, respectively. Transcapillary escape rate of albumin (TERalb) and hyaluronan catabolism were assessed as measures of vascular permeability.ResultsBoth sublingual dimensions (0.64 [0.57–0.75] μm vs 0.78 [0.71–0.85] μm, p < 0.05, medians [interquartile range]) and retinal glycocalyx dimensions (5.38 [4.88–6.59] μm vs 8.89 [4.74–11.84] μm, p < 0.05) were reduced in the type 2 diabetes group compared with the controls whereas TERalb was increased (5.6 ± 2.3% vs 3.7 ± 1.7% in the controls, p < 0.05). In line with these findings, markers of hyaluronan catabolism were increased with diabetes (hyaluronan 137 ± 29 vs 81 ± 8 ng/ml and hyaluronidase 78 ± 4 vs 67 ± 2 U/ml, both p < 0.05). Sulodexide increased both the sublingual and retinal glycocalyx dimensions in participants with diabetes (to 0.93 [0.83–0.99] μm and to 5.88 [5.33–6.26] μm, respectively, p < 0.05). In line, a trend towards TERalb normalisation (to 4.0 ± 2.3%) and decreases in plasma hyaluronidase (to 72 ± 2 U/ml, p < 0.05) were observed in the diabetes group.Conclusion/interpretationType 2 diabetes is associated with glycocalyx perturbation and increased vascular permeability, which are partially restored following sulodexide administration. Further studies are warranted to determine whether long-term treatment with sulodexide has a beneficial effect on cardiovascular risk.Trial registration www.trialregister.nl NTR780/http://isrctn.org ISRCTN82695186FundingAn unrestricted Novartis Foundation for Cardiovascular Excellence grant (2006) to M. Nieuwdorp/E. S. G. Stroes, Dutch Heart Foundation (grant number 2005T037)

Autonomic neuropathy predisposes to rosiglitazone-induced vascular leakage in insulin-treated patients with type 2 diabetes: a randomised, controlled trial on thiazolidinedione-induced vascular leakage

Aims/hypothesisThe mechanism of fluid-related complications caused by thiazolidinedione derivatives is unclear. One potential mechanism is thiazolidinedione-induced arterial vasodilatation, which results in vascular leakage and a fall in blood pressure, normally counterbalanced by sympathetic activation and subsequent renal fluid retention. We hypothesised that thiazolidinedione-induced vascular leakage will be particularly prominent in patients with autonomic neuropathy.MethodsWe conducted a randomised, double-blind, placebo-controlled, parallel study in 40 patients with type 2 diabetes on insulin treatment recruited from a university medical centre. The randomisation was performed by a central office using a randomisation schedule. Both treatment groups, placebo (n = 21) and rosiglitazone (n = 19), were stratified for sex and level of autonomic neuropathy as assessed by Ewing score (<2.5 or ≥2.5). We investigated the effects of 16 weeks of treatment with rosiglitazone 4 mg twice daily on vascular leakage (transcapillary escape rate of albumin, TERalb), body weight, extracellular volume and plasma volume.ResultsThirty-nine patients were included in the analysis. In patients with high Ewing scores (n = 16), rosiglitazone increased TERalb significantly (ΔTERalb: rosiglitazone +2.43 ± 0.45%/h, placebo −0.11 ± 0.15%/h, p = 0.002), while rosiglitazone had no effect in the patients with low Ewing scores (n = 23). Rosiglitazone-induced increases in TERalb and Ewing score at baseline were correlated (r = 0.65, p = 0.02). There was no correlation between Ewing score and rosiglitazone-induced changes in fluid variables. One subject was withdrawn from the study because of atrial fibrillation.Conclusions/interpretationRosiglitazone may increase vascular leakage in insulin-treated patients with type 2 diabetes with autonomic neuropathy. Autonomic neuropathy did not exaggerate rosiglitazone-induced fluid retention. Therefore, autonomic neuropathy should be considered as a risk factor for thiazolidinedione-induced oedema, not for thiazolidinedione-induced fluid retention.Trial registrationClinicalTrials.gov NCT00422955FundingGlaxoSmithKline

Vascular Permeability, Blood Pressure, and Organ Damage in Primary Hypertension

Sub-clinical organ damage is a strong independent predictor of cardiovascular mortality in primary hypertension, and its changes over time parallel those in risk of cardiovascular events. A better understanding of the pathogenetic mechanisms underlying the development of target organ damage may help us devise more effective therapeutic strategies. We therefore investigated the relationship between the presence of organ damage and some of its potential determinants, such as blood pressure severity and early atherosclerotic abnormalities. Thirty-seven untreated, non-diabetic hypertensive patients were enrolled. Target organ damage was assessed by albuminuria and left ventricular mass index; systemic vascular permeability was evaluated by transcapillary escape rate of albumin (TERalb); and blood pressure was measured by 24h ambulatory blood pressure monitoring. The albumin-to-creatinine ratio and left ventricular mass index were directly related to TERalb (r = 0.48, p = 0.003 and r = 0.39, p < 0.020, respectively) and 24-h systolic blood pressure values (r = 0.54, p < 0.001; r = 0.60, p < 0.001). The simultaneous occurrence of increased blood pressure load and TERalb was associated with higher left ventricular mass index values (p = 0.012) and entailed an increased risk of having at least one sign of damage (chi2 = 17.4; p < 0.001). Logistic regression analysis showed that the risk of presenting at least one sign of organ damage increased more than ten-fold when TERalb was above the median and more than five-fold with each 10 mmHg increase in 24-h systolic blood pressure. Blood pressure load and vascular permeability are potentially modifiable factors that are independently associated with the occurrence of sub-clinical signs of renal and cardiac damage in hypertensive patients.

The Vascular Wall and the Haemostatic Balance in Type 1 Diabetic Patients with Nephropathy

In type 1 diabetes a main burden of complications is related to presence of nephropathy. A generalised vascular damage in patients with nephropathy has been proposed to explain this relation. A procoagulant state in type 1 diabetes patients can be related to the transcapillary escape rate of albumin in patients without nephropathy. There is however to date, no consistently demonstrated further procoagulant derangement in patients with nephropathy, but this may be due to a methodological shortcoming caused by urinary loss of the coagulation marker measured. A significant heparin-induced vitronectin release in patients with nephropathy can reflect procoagulant activity in these patients. The procoagulant state in normoalbuminuric type 1 diabetes is followed by an increased activity of tissue- type plasminogen activator, and this potential compensation of the procoagulant state is absent in nephropathy. Haemostatic balance could be achieved at a higher level of fibrin accumulation or a higher activity of a fibrin surface exposed to the circulation. Data from a venous occlusion study indicate that plasminogen activator inhibitor 1 (PAI 1), fibronectin and von Willebrand factor were significantly captured by the subendothelial matrix in patients with nephropathy. Antithrombin with specific affinity for heparan sulphate was not significantly captured and this could be a consequence of a deficiency of heparan sulphate in the subendothelial matrix. Heparin is able to reduce urinary albumin excretion in patients with incipient nephropathy, and although the mechanism for this effect is unknown, it is theoretically in accordance with the hypothesis that heparan sulphate is a key in the development of diabetic nephropathy. Future long-term studies, perhaps with oral heparins, should be performed to investigate whether such treatment, added to the current treatment set in guidelines, could further protect patients from progression in diabetic nephropathy. Such studies could also address whether generalised vascular damage can be modified.

ACE gene insertion/deletion polymorphism modulates capillary permeability in hypertension

A D/D (deletion/deletion) polymorphism within the ACE (angiotensin 1-converting enzyme) gene increases the risk of microalbuminuria, a predictor of atherosclerotic vascular disease, in essential hypertension. It is unknown, however, whether this genetic profile is accompanied by disturbed macromolecular permeability of systemic capillary endothelium, possibly in the context of generalized endothelial dysfunction. In the present study, the ACE gene polymorphism was determined by PCR in 79 never-treated uncomplicated hypertensive men and 16 normotensive men as controls. Evaluation variables were TERalb (transcapillary escape rate of albumin; the 1-h decline rate of intravenous (125)I-albumin, a measure of integrity of systemic capillary endothelium), albuminuria and forearm vasodilation to intra-arterial acetylcholine, an index of NO (nitric oxide)-mediated vasomotion, in addition to a series of sensitive parameters of albumin permeation (blood pressure, metabolic status and smoking habits). Analyses were done by comparing D/D homozygotes with grouped I/D (insertion/deletion) and I/I (insertion/insertion) subjects. TERalb was higher in D/D hypertensives, who had higher albuminuria, more frequent microalbuminuria and comparable forearm responsiveness to intra-arterial acetylcholine. Fasting glucose and insulin, insulin sensitivity, 24-h blood pressure, smoking habits and metabolic parameters did not differ between the two groups. TERalb and urine albumin values were positively associated in the hypertensive subjects. In conclusion, ACE D/D homozygosis, independently of several confounding factors, associates with higher TERalb in men with essential hypertension. This may reflect noxious genetic influences on systemic vascular permeability, a critical control mechanism for atherogenesis in the absence of grossly impaired NO-mediated arteriolar responsiveness. The parallel behaviour of TERalb and albuminuria suggests some shared genetically mediated determinant of renal and systemic microvascular abnormalities in hypertension.

Microalbuminuria, Blood Pressure Load, and Systemic Vascular Permeability in Primary Hypertension

Microalbuminuria, a powerful predictor of cardiovascular events, is thought to reflect widespread subclinical vascular abnormalities. To explore the pathogenesis of increased urinary albumin excretion in primary hypertension we evaluated systemic capillary permeability and ambulatory blood pressure (BP) measurement in two groups of matched untreated patients with (n = 11) and without (n = 29) microalbuminuria. Albuminuria was measured as the mean of albumin-to-creatinine ratio (ACR) in three nonconsecutive first morning urine samples. Systemic capillary permeability was evaluated by transcapillary escape rate of albumin (TERalb) (ie, the 1-h decline rate of intravenous (125)I-albumin). Twenty-four-hour ambulatory BP, renal hemodynamics, and hormones of the renin-angiotensin-aldosterone system (RAAS) were also assessed. Patients with microalbuminuria showed greater body mass index (BMI) (P < .04), higher 24-h systolic and diastolic BP levels (P = .02), and higher capillary permeability to albumin (P < .02) as compared to normoalbuminurics. Renal hemodynamics and RAAS hormones were similar in the two groups. Univariate analysis showed that urinary ACR was related to ambulatory pressure components (P < .02), TERalb (r = 0.31, P < .05), smoking habits (r = 0.36, P = .02), and left ventricular mass index (LVMI) (r = 0.57, P < .001) among the whole study group. Logistic regression analysis showed that each 1% increment in TERalb or 10 mm Hg increase in systolic BP entailed an almost three times higher risk of having microalbuminuria. Microalbuminuria is associated with greater systemic BP load and increased vascular permeability in patients with primary hypertension.

Fluid Retention and Vascular Effects of Rosiglitazone in Obese, Insulin-Resistant, Nondiabetic Subjects

The use of thiazolidinedione (TZD) derivatives is associated with fluid retention, especially when combined with insulin. Because TZDs improve the metabolic effect of insulin, they may also reverse the blunted vascular response to insulin. We hypothesize that improvement of the action of insulin on vascular tone or permeability is the key mechanism of TZD-related fluid retention. In a randomized, double-blind, placebo-controlled, cross-over study in 18 obese, nondiabetic subjects with features of the metabolic syndrome, we investigated the effects of a 12-week treatment with 4 mg rosiglitazone twice a day on glucose disposal, hemodynamics (including forearm vasoconstrictor response to nitric oxide [NO]), synthase inhibition by N-monomethyl-L-arginine-acetate (L-NMMA), vascular permeability (transcapillary escape rate of albumin), and plasma volume during a hyperinsulinemic-euglycemic clamp (120 min, 120 mU/m(2) per min). As expected, rosiglitazone increased the glucose infusion rate during clamping. However, neither vascular permeability nor forearm blood flow response to hyperinsulinemia or L-NMMA was affected by rosiglitazone. Compared with placebo, rosiglitazone decreased diastolic blood pressure by 5 mmHg (95% CI 2.35-6.87, P = 0.0005) and increased plasma volume by 255 ml/1.73 m(2) (80-430, P = 0.007). Interestingly, the positive effect of rosiglitazone on glucose disposal correlated with change in foot volume (R(2) = 0.53, P = 0.001). Rosiglitazone improved insulin sensitivity but had no effect on NO-dependent vasodilatation in the forearm or vascular permeability in obese, insulin-resistant, nondiabetic subjects. As such, TZD-related fluid retention was not caused by improvement of the vascular actions of insulin. Nonetheless, rosiglitazone-induced improvement in insulin sensitivity appears to be correlated to edema formation.

Progesterone increases plasma volume independent of estradiol

Adequate plasma volume (PV) and extracellular fluid (ECF) volume are essential for blood pressure and fluid regulation. We tested the hypotheses that combined progesterone (P(4))-estrogen (E(2)) administration would increase ECF volume with proportional increases in PV, but that P(4) would have little independent effect on either PV or ECF volume. We further hypothesized that this P(4)-E(2)-induced fluid expansion would be a function of renin-angiotensin-aldosterone system stimulation. We suppressed P(4) and E(2) with a gonadotropin-releasing hormone (GnRH) antagonist in eight women (25 +/- 2 yr) for 16 days; P(4) (200 mg/day) was added for days 5-16 (P(4)) and 17beta-estradiol (2 x 0.1 mg/day patches) for days 13-16 (P(4)-E(2)). On days 2 (GnRH antagonist), 9 (P(4)), and 16 (P(4)-E(2)), we estimated ECF and PV. To determine the rate of protein and thus water movement across the ECF, we also measured transcapillary escape rate of albumin. In P(4), P([P(4)]) increased from 2.5 +/- 1.3 to 12.0 +/- 2.8 ng/ml (P < 0.05) with no change in P([E(2)]) (21.5 +/- 9.4 to 8.6 +/- 2.0 pg/ml). In P(4)-E(2), plasma concentration of P(4) remained elevated (11.3 +/- 2.7 ng/ml) and plasma concentration of E(2) increased to 254.1 +/- 52.7 pg/ml (P < 0.05). PV increased during P(4) (46.6 +/- 2.5 ml/kg) and P(4)-E(2) (48.4 +/- 3.9 ml/kg) compared with GnRH antagonist (43.3 +/- 3.2 ml/kg; P < 0.05), as did ECF (206 +/- 19, 244 +/- 25, and 239 +/- 27 ml/kg for GnRH antagonist, P(4), and P(4)-E(2), respectively; P < 0.05). Transcapillary escape rate of albumin was lowest during P(4)-E(2) (5.8 +/- 1.3, 3.5 +/- 1.7, and 2.2 +/- 0.4%/h for GnRH antagonist, P(4), and P(4)-E(2), respectively; P < 0.05). Serum aldosterone increased during P(4) and P(4)-E(2) compared with GnRH antagonist (79 +/- 17, 127 +/- 13, and 171 +/- 25 pg/ml for GnRH antagonist, P(4), and P(4)-E(2), respectively; P < 0.05), but plasma renin activity and plasma concentration of ANG II were only increased by P(4)-E(2). This study is the first to isolate P(4) effects on ECF; however, the mechanisms for the ECF and PV expansion have not been clearly defined.

Renal dysfunction as a novel risk factor: Microalbuminuria and cardiovascular risk

only for elevated glucose or BMI values; the correlation extends well into the range of normal values. Apparently, the metabolic syndrome and microalbuminuria are tightly correlated with each other. This relation is of considerable interest because in patients with renal disease insulin resistance is found even in the very early stages [10], and even when GFR is still within the normal range (unpublished observations). Conversely, in a population sample it was found that insulin resistance (according to the HOMA index) was associated with a higher risk of chronic kidney disease [11]. The information obtained from microalbuminuria cannot be replaced by estimating the glomerular filtration rate. Although the reports in the literature are not entirely consistent, the study in Groningen showed that with increasing quantiles of urinary albumin excretion, the creatinine clearance tended to be higher and was lower only in the uppermost quantiles [12]. Although the creatinine clearance is not a reliable index of glomerular filtration, this observation would be plausible in view of a similar relation between GFR and albuminuria noted previously in diabetic patients [13]. There has been much discussion whether microalbuminuria reflects primarily a generalized endothelial cell dysfunction, as suggested by the Steno hypothesis [14], or whether it reflects a podocyte defect, as proposed more recently [15]. The observation that the rate of albumin escape from the plasma space is increased in patients with microalbuminuria [16] argues for the former possibility. The observation that the risk of being microalbuminuric was significantly higher for carriers of the Q-genotype of the 229 polymorphism of the podocin gene at any given level of body mass index or other correlates of microalbuminuria is more in favor of a podocyte problem [15].

Altered Transcapillary Escape of Albumin and Microalbuminuria Reflects Two Different Pathogenetic Mechanisms

We studied the following in normo- and microalbuminuric hypertensive type 2 diabetic patients: 1) transcapillary escape rate of albumin (TERalb) and 2) expression of mRNA slit diaphragm and podocyte proteins in renal biopsies. Normoalbuminuric subjects had renal cancer, and kidney biopsy was performed during surgery. TERalb was evaluated by clearance of (125)I-albumin. Real-time PCR of mRNA slit diaphragm was measured in kidney specimens. Albumin excretion rate (AER) was by definition lower in normoalbuminuric subjects than in microalbuminuric subjects with typical diabetic glomerulopathy (group 1), in microalbuminuric subjects with normal or near-normal glomerular structure (group 2), and in microalbuminuric subjects with atypical diabetic nephropathy (group 3). This classification was based on light microscopy analysis of renal tissue. TERalb (%/h) was similar in normoalbuminuric and microalbuminuric group 1, 2, and 3 diabetic patients (medians: 14.1 vs. 14.4 vs. 15.7 vs. 14.9, respectively) (ANOVA, NS). mRNA expression of slit diaphragm proteins CD2AP, FAT, Actn 4, NPHS1, and NPHS2 was higher in normoalbuminuric patients than in microalbuminuric patients (groups 1, 2, and 3) (ANOVA, P < 0.001). All diabetic patients had greater carotid artery intimal thickness than normal control subjects using ultrasound technique (ANOVA, P < 0.01). In conclusion, the present study suggests that microalbuminuria identifies a subgroup of hypertensive type 2 diabetic patients who have altered mRNA expression of slit diaphragm and podocyte proteins, even before glomerular structure shows abnormalities using light microscopy analysis. On the contrary, altered TERalb and increased carotid artery intimal thickness are shown by all hypertensive type 2 diabetic patients, both with normal and altered patterns of AER.