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Biomedical subjects

George A Kaysen

Publications and source records attributed to George A Kaysen.

At least 19 recordsLinked to original sources
PubMed2007

Disorders in high-density metabolism with insulin resistance and chronic kidney disease.

Cardiovascular risk increases with each decrement in renal function. Low-density lipoprotein (LDL) cholesterol levels are not associated with increased mortality, but high-density lipoprotein (HDL) levels are inversely associated with cardiovascular risk. Lipoprotein composition with increased abundance of small dense LDL and HDL and reduced levels of more buoyant isoforms is similar to what is found in states of insulin resistance and in the metabolic syndrome (MS). In both cases, high triglyceride levels are associated with reduced HDL levels. Chronic kidney disease (CKD) is itself associated with increasing insulin resistance as renal function fails. In both instances, decreased levels of apo A-I and apo A-II are a consequence of increased fractional catabolic rate (FCR), resulting from a predominance of small HDL particles. HDL maturation is impaired in CKD through decreased activity of lecithin:cholesterol acyltransferase (LCAT), and increased cholesterol ester transfer protein (CETP) activity in MS shuttles triglycerides back into HDL, thereby destabilizing it. Whether insulin resistance is entirely responsible for disorders of HDL metabolism in CKD, or whether the process is a result of unrelated pathophysiology, is currently unknown.

Apolipoproteins↗
PubMed2006

Evidence that C-reactive protein or IL-6 are not surrogates for all inflammatory cardiovascular risk factors in hemodialysis patients.

BACKGROUND/AIMS: In otherwise healthy adults, high C-reactive protein (CRP) levels are associated with cardiovascular disease and have been linked to an inflammatory state. The presence of vascular disease is also associated with increased expression of adhesion molecules, including soluble intercellular adhesion molecule (sICAM), vascular endothelial growth factor (VEGF) and leukocyte-derived myeloperoxidase (MPO). These associations suggest potential mechanisms whereby inflammation may injure the vascular endothelium, but the recognition of how these mediators act in concert remain poorly characterized. That the prevalence of atherosclerosis and markers of inflammation are increased in renal failure patients suggests that inflammation causes accelerated vascular disease. METHODS: In hemodialysis patients, we examined the relationships between plasma CRP and sICAM, VEGF and MPO longitudinally. We determined whether episodes of a high CRP value were paralleled by simultaneous increases in mediators of inflammatory injury or molecules associated with endothelial cell adhesion or growth and whether CRP levels correlated with those of VEGF and MPO. RESULTS: Episodic increases in CRP were accompanied by higher levels of VEGF, sICAM and MPO. However, there was no correlation between serum CRP levels or other acute phase proteins and either MPO or VEGF, nor was there a constant temporal relationship between MPO and CRP. By contrast, MPO and VEGF levels were closely correlated with one another during episodes of inflammation (p = 0.0001), and CRP and interleukin-6 levels were also correlated. Increases in MPO tended to be restricted to patients with grafts or catheters, and not those with AV fistulas. CONCLUSIONS: These results suggest that high plasma levels of CRP or other acute phase proteins in cross-sectional studies should be interpreted cautiously when defining mechanisms underlying cardiovascular disease in the hemodialysis patient population. One, or more than one inflammatory repertoire may be activated, one involving hepatic acute phase proteins and the other neutrophil activation and each may contribute separately to outcomes. Better prognostic information may be obtained by measurement of more markers than CRP alone, such as MPO and VEGF.

Adolescent↗
PubMed2006

Challenging the validity of the EPO index.

BACKGROUND: With use of recombinant erythropoietin (EPO) and intravenous iron, the majority of hemodialysis patients can achieve target hemoglobin concentrations. EPO resistance arises as a consequence of inflammation and other processes that can adversely affect survival. We hypothesized that the EPO dose-hematocrit (EPO/Hct) ratio, also known as the EPO index, may be a surrogate for inflammation and that greater EPO/Hct ratios would be associated with decreased survival. METHODS: We used proportional hazards regression models and time-varying logistic models to analyze the association between EPO index and survival in US hemodialysis patients initiating hemodialysis therapy between January 1, 1999, and December 31, 2000, and followed up for up to 3 years until December 31, 2001. RESULTS: We found an unexpected and consistent association between greater EPO index and survival in all models. The associations of EPO/Hct ratio were most prominent at intermediate Hct values and with longer dialysis vintage. Iron administration was associated with a lower risk for death independent of Hct. Conversely, greater average prior EPO dose was associated with a greater risk for death. CONCLUSION: EPO resistance may be reflected better by total cumulative EPO dose than the EPO/Hct ratio. The mechanism(s) responsible for the association between a greater EPO/Hct ratio and survival remains to be established, but may be a result of nonerythrogenic effects of EPO.

Adult↗
PubMed2006

Cerebrovascular disease in maintenance hemodialysis patients: results of the HEMO Study.

BACKGROUND: Cerebrovascular disease (CBVD) in hemodialysis patients is associated with significant morbidity and mortality. A secondary analysis of CBVD in the Hemodialysis (HEMO) Study was performed. Specific objectives were to: (1) determine risk factors for the presence of CBVD at baseline, (2) assess risk factors for the subsequent occurrence of cerebrovascular deaths, and (3) analyze the effects of dose and flux on cerebrovascular mortality. METHODS: The HEMO Study was a randomized multicenter study evaluating the effects of high-dose versus standard-dose and high-flux versus low-flux hemodialysis. There were 1,846 patients enrolled, with a mean follow-up of 2.84 years. RESULTS: Factors associated with the baseline presence of CBVD included age (P < 0.0001), presence of any cardiac disease (P < 0.0001), and diabetes mellitus (P < 0.0001). There were 65 deaths caused by CBVD (event rate, 1.2/100 patient-years). Multivariate Cox regression using a backward-variables selection procedure showed that diabetes, lower albumin level, greater hematocrit, and lower body mass index at baseline were associated significantly with subsequent CBVD death. There was no effect of flux or dose on overall rate of CBVD deaths. However, an interaction was found between baseline CBVD status and flux intervention on CBVD death (P = 0.016). In the subgroup of patients without the baseline presence of CBVD, high-flux dialysis was associated with a lower risk for death caused by CBVD (P = 0.016). A borderline interaction between years of dialysis therapy and flux on subsequent CBVD death was detected (P = 0.05). The beneficial effect of high flux was evident in those on hemodialysis therapy for longer than 3.7 years (P = 0.012). CONCLUSION: High flux was associated with decreased CBVD mortality in those without known CBVD at baseline and those on hemodialysis therapy for longer than 3.7 years. This secondary analysis strengthens, but does not prove, the hypothesis that high-flux treatment may attenuate the death rate from vascular disease.

Aged↗
PubMed2006

Association between inflammation and malnutrition as risk factors of cardiovascular disease.

Cardiovascular disease is the leading cause of death among dialysis patients. The relative risk of mortality increases as serum albumin concentration and body mass index decline. While these are generally associated with nutritional status, inflammation causes sarcopenia and decreased albumin concentration by reducing synthesis of proteins and increasing their catabolic rate. While inflammation can arise from atherosclerotic blood vessels, systemic inflammation from any source can alter the vascular endothelium and plasma protein composition in ways that promotes vascular injury. High-density lipoprotein synthesis is decreased and the high-density lipoprotein present is less capable of reducing inflammation. Activation of neutrophils favors lipoprotein oxidation. Surprisingly, while obesity is associated with cytokine production in patients without renal failure, as well as among dialysis patients, increased body mass index, whether reflecting muscle mass or adipose tissue, is associated with a decline in mortality rates.

Adipose Tissue↗
PubMed2005

Graded effects of proteinuria on HDL structure in nephrotic rats.

Nephrotic syndrome is characterized by increased triglycerides resulting from decreased clearance of VLDL and chylomicrons. These triglyceride-rich lipoproteins are structurally altered by interaction with HDL derived from animals with proteinuria and not as a consequence of hypoalbuminemia. HDL isolated from rats with massive proteinuria is depleted in apolipoprotein E (apoE). It is unknown at what threshold of urinary albumin loss HDL structure is altered, and it is unknown what effects proteinuria has on apolipoproteins other than apoE. Two models of albuminuria were used in Sprague-Dawley rats: Adriamycin and passive Heymann nephritis (HN). The adriamycin group was divided into minimal albumin excretion (MAE) and intermediate albumin excretion (MAE, 1 to 40; intermediate albumin excretion, 60 to 210 mg/d per 100 g body wt). Urinary albumin excretion exceeded 300 mg/d per 100 g body wt in the HN rats. HDL apolipoprotein composition was analyzed with SDS-PAGE densitometry and liquid chromatography-time of flight mass spectrometer mass spectrometry. HDL apoA-IV content relative to apoA-I was reduced at all levels of albuminuria (P < 0.0001). ApoE was not reduced in MAE but was significantly reduced in IAE (72%; P < 0.001). By contrast, apoA-II and apoC-III were each significantly increased with increasing UAE. ApoA-IV and apoE were decreased to approximately 10% of control in HDL isolated from rats with HN, whereas apoA-II, apoC-II, and apoC-III were each significantly increased relative to apoA-I. HDL is structurally altered by levels of albuminuria that are insufficient to change serum albumin levels and is progressively altered as albuminuria increases.

Albuminuria↗
PubMed2005

The spectrum of infection-related morbidity in hospitalized haemodialysis patients.

BACKGROUND: Infection is a common cause of mortality and morbidity in haemodialysis patients. Few prospective studies have examined the clinical consequences of infection-related hospitalizations in haemodialysis patients or the risk factors predictive of clinical outcomes. METHODS: The outcomes of all first infection-related hospitalizations of patients enrolled in the HEMO Study were categorized in terms of mortality, requirement for intensive care unit (ICU) stay and length of hospitalization. In addition, the association of hospitalization outcomes with clinical and laboratory parameters was evaluated. RESULTS: Among the 783 first infection-related hospitalizations, 57.7% had a severe outcome (death, ICU stay or hospitalization >/=7 days). The likelihood of a severe outcome increased with patient age (P<0.0001) and with decreased serum albumin (P<0.001). The frequency of a severe outcome varied greatly by infectious disease category (P<0.001), being highest for cardiac infections (95.6%) and infection of unknown source (68.4%), and lowest for urinary tract infections (35.5%) and access-related infections (43.8%). On multivariate analysis, hospitalization outcome was independently associated with patient age, serum albumin and disease category, but not with the randomized Kt/V or flux, gender, race or diabetic status. CONCLUSION: In summary, infection-related hospitalizations are associated with substantial morbidity. Patient age, serum albumin and infectious disease category are independently correlated with the hospitalization outcome, and can be used to estimate the likelihood of serious outcomes at the time of hospital admission.

Adult↗
PubMed2005

Effects of inflammation on plasma composition and endothelial structure and function.

Changes in plasma protein composition normally associated with malnutrition, specifically hypoalbuminemia and reduced levels of tranferrin and prealbumin, usually only occur in the presence of preterminal starvation in the absence of inflammation. Thus, reduced levels of any of these proteins suggest that the inflammatory response has been activated. Inflammation also alters lipoprotein structure and function, and oxidation of low-density lipoprotein (LDL). This decreases high-density lipoprotein (HDL) levels and reduces its capacity to function as an antioxidant, and increases the levels of proteins, such as fibrinogen, associated with vascular disease. Cytokines and acute phase proteins, such as C-reactive protein (CRP), also up-regulate expression of adhesion molecules on the vascular endothelium, making them more effective targets for macrophage adhesion. Leukocyte-derived myeloperoxidase functions as an "NO oxidase" in the inflamed vasculature and contributes to decreased NO bioavailability and compromises vascular reactivity. The link between inflammation and apparent malnutrition explains the relationship between low levels of albumin, prealbumin, and transferrin with subsequent cardiovascular risk.

Atherosclerosis↗
PubMed2005

Assessment of body composition in long-term hemodialysis patients: rationale and methodology.

Protein-energy malnutrition is seen in patients with advanced stages of chronic kidney disease (CKD) and is even more pronounced in patients receiving long-term hemodialysis treatment. Both entities have great impact on patient morbidity and mortality. Analysis of body composition is an integral part of nutritional assessment and includes the estimation of muscle, fat, and fat-free mass, as well as the extracellular water compartment. Clinical assessment of these compartments is difficult, and gold-standard methods such as tracer dilution, magnetic resonance imaging, and dual-energy x-ray absorptiometry are expensive, cumbersome, and rarely available. We report an ongoing study of body composition in hemodialysis patients involving deuterium and sodium bromide dilution, total body potassium counting, magnetic resonance imaging, whole-body and segmental bioimpedance spectroscopy, and anthropometry. The goals of the study are (1) to validate bioimpedance technology against gold-standard methods for assessment of the various body compartments, (2) to directly quantify visceral adipose tissue mass, a potential source of cytokine production (adipokines) promoting chronic inflammation, and to study its relation to inflammatory markers, and (3) to directly quantify visceral organ mass and to study its relation to uremia toxin generation as assessed by protein catabolic rate and resting energy expenditure. Preliminary results based on up to 40 hemodialysis patients are reported.

Adipose Tissue↗
PubMed2005

Estimation of total-body and limb muscle mass in hemodialysis patients by using multifrequency bioimpedance spectroscopy.

BACKGROUND: Skeletal muscle mass can be measured noninvasively with magnetic resonance imaging (MRI), but this is time-consuming and expensive. OBJECTIVE: We evaluated the use of multifrequency bioimpedance spectroscopy (BIS) measurements of intracellular volume (ICV) to model total-body skeletal muscle mass (TBMM) and limb skeletal muscle mass in hemodialysis patients. DESIGN: TBMM was measured by MRI in 20 male and 18 female hemodialysis patients with a median (range) age of 54 y (33-73 y), weight of 78.9 kg (43.2-120 kg), and body mass index (BMI; in kg/m2) of 27.3 (19.4-46.6). We measured total body water (TBW) by using D2O dilution, extracellular volume (ECV) as bromide space, and ICV as TBW minus bromide space. Total body potassium (TBK) measured as 40K was used as an independent model of TBMM. BIS was used to measure whole-body TBW (ankle to wrist) and TBW in the arms and legs. BIS-estimated ICV was used to construct models to calculate limb muscle mass and TBMM. The latter was compared with models derived from isotopic methods. RESULTS: BIS yielded a model for TBMM [TBMM = 9.52 + 0.331 x ICV + 2.77 (male) + 0.180 x weight (kg) - 0.133 x age] (R2 = 0.937, P < 0.0001) as precise as TBK-measured TBMM [TBMM = 1.29 + 0.00453 x TBK (mEq) + 1.46 (male) + 0.144 x weight (kg) - 0.0565 x age] (R2 = 0.930, P < 0.0001) or isotopic methods. BIS models were also developed for measuring leg and arm muscle mass. CONCLUSION: BIS provides an estimate of TBMM that correlates well with isotopic methods in approximating values obtained by MRI and can be used to estimate limb muscle mass.

Adult↗
PubMed2005

Prealbumin, mortality, and cause-specific hospitalization in hemodialysis patients.

BACKGROUND: Prealbumin (transthyretin) is a hepatic secretory protein thought to be important in the evaluation of nutritional deficiency and nutrition support. Prior studies have suggested that the serum prealbumin concentration is independently associated with mortality in hemodialysis patients, even with adjustment for serum albumin and other nutritional parameters. METHODS: To determine whether prealbumin was independently associated with mortality and morbidity (cause-specific hospitalization) in hemodialysis patients, we analyzed data on 7815 hemodialysis patients with at least one determination of serum prealbumin during the last three months of 1997. Unadjusted, case mix-adjusted, and multivariable-adjusted relative risks of death were calculated for categories of serum prealbumin using proportional hazards regression. We also determined whether the prealbumin concentration was associated with all-cause, cardiovascular, infection-related, and vascular access-related hospitalization. RESULTS: The relative risk (RR) of death was inversely related to the serum prealbumin concentration. Relative to prealbumin > or =40 mg/dL, the adjusted RRs of death were 2.41, 1.85, 1.49, and 1.23 for prealbumin <15, 15-20, 20-25, and 25-30 mg/dL, respectively. The adjusted RRs of hospitalization due to infection were 2.97, 1.95, 1.81, and 1.61 for prealbumin <15, 15-20, 20-25, and 25-30 mg/dL, respectively. The adjusted RRs of vascular access-related hospitalization were 0.48, 0.52, 0.58, and 0.71 for prealbumin <15, 15-20, 20-25, and 25-30 mg/dL, respectively. While serum albumin was strongly associated with mortality and all-cause hospitalization, it was not associated with hospitalization due to infection, and lower levels were associated with higher rather than lower rates of vascular access-related hospitalization. CONCLUSION: In hemodialysis patients, lower prealbumin concentrations were associated with mortality and hospitalization due to infection, independent of serum albumin and other clinical characteristics. Higher prealbumin concentrations were associated with vascular access-related hospitalization. In light of these findings, more intensive study into the determinants and biological actions of prealbumin (transthyretin) in end-stage renal disease is warranted.

Aged↗
PubMed2005

The pharmacokinetics of etanercept in patients with end-stage renal disease on haemodialysis.

Inflammation is strongly associated with malnutrition and cardiovascular risk in patients with chronic renal failure on haemodialysis (HD). The acute-phase inflammatory response, defined by the increased synthesis of positive acute-phase proteins, is stimulated by the production of such cytokines as interleukin 6 (IL-6), interleukin 1 (IL-1) and tumour necrosis factor-alpha TNF-alpha The availability of cytokine antagonists allows testing of the hypothesis that suppression of inflammation reverses the malnutrition-inflammation syndrome in HD patients. Etanercept is a soluble TNF-alpha receptor fusion protein used to suppress inflammation in rheumatoid and psoriatic arthritis. Its metabolism in HD patients is unknown. In a study designed to test the safety and pharmacokinetics of etanercept in HD patients, etanercept was administered to six HD patients with albumin levels above 4.2 g dL(-1) and C-reactive protein levels <5 mg L(-1) (five men, one woman, age range 34-59 years). Etanercept (25 mg) was administered subcutaneously twice weekly immediately after dialysis for 13-16 weeks. Etanercept concentrations were measured pre- and post-dialysis by ELISA. Concentrations were compared graphically to assess whether, firstly, dialysis affects etanercept apparent clearance and, secondly, etanercept kinetics were similar between HD patients and the more extensively studied psoriasis population with normal renal function (PS). The second stage examined model-based parameter predictions of the terminal elimination rate constant (k) for HD patients. Steady-state etanercept levels were comparable between HD and PS patients. Treatment with HD had no effect on etanercept levels. When etanercept was discontinued, the terminal rate constant for HD patients was not significantly different from that observed in PS patients. No adverse effects were noted during the 3-month treatment phase and subsequent 6-month follow-up. Albumin and C-reactive protein levels did not change in these non-inflamed patients during the study period. The pharmacokinetics of etanercept in patients with chronic renal failure on HD are similar to patients with normal renal function. It is, therefore, feasible to administer etanercept to HD patients without adjusting the dose.

Adult↗
PubMed2004

Inflammation: cause of vascular disease and malnutrition in dialysis patients.

Inflammation occurs in response to tissue injury or the presence of foreign antigens and is important in the mobilization of specific immunologic and nonimmunologic defenses against injury. The vascular endothelium is altered to allow immune competent cells to access the interstitial space. Muscle and visceral proteins are catabolized and the amino acids are used either to supply energy or as substrates for the production of acute-phase proteins that play a role in defense. Restoration of muscle mass is impaired while inflammation is on going. Lipids are mobilized. Although serving a vital role in allowing host survival from acute injury or infection, if unimpeded, or if triggered inappropriately, the acute-phase response may instead lead to increased vascular injury and progressive loss of muscle and visceral protein pools causing malnutrition. Markers of inflammation (C reactive protein [CRP] or interleukin-6 [IL-6] levels) are associated with cardiovascular risk in the general population and in dialysis patients. Hypoalbuminemia also is associated with cardiovascular risk in dialysis patients. Although albumin is considered a marker of nutrition, changes in albumin levels are associated with increased levels of acute-phase proteins. Persistent changes in albumin levels are caused by reduced albumin synthesis associated with inflammation and not decreased normalized protein catabolic rate. The cause(s) of inflammation must be identified and treated to resolve malnutrition and reduce cardiovascular risk.

Humans↗
PubMed2004

The influence of patient- and facility-specific factors on nutritional status and survival in hemodialysis.

BACKGROUND: Parameters of nutritional status, including serum albumin, serum creatinine, and body mass index (BMI), are powerful predictors of mortality and hospitalization in patients with end stage renal disease (ESRD). Patient-specific characteristics and facility-related practice patterns modify certain parameters of nutritional status. We aimed to determine whether patient and facility characteristics modify the risk profiles associated with malnutrition in hemodialysis patients. METHODS: We analyzed data on 5,234 prevalent hemodialysis patients from the Dialysis Morbidity and Mortality Study (DMMS) Wave 1 for whom information on demographic, clinical, nutritional, and facility-related characteristics were available. We evaluated the associations among facility characteristics and serum albumin, serum creatinine, and BMI, adjusting for the effects of age, sex, race/ethnicity, diabetes, and dialysis vintage. We determined correlates of mortality and hospitalization, focusing on nutritional parameters, facility effects, and the interactions among patient-specific and facility-specific characteristics, albumin, creatinine, and BMI. RESULTS: Serum albumin was lower with older age, diabetes, nonblack race, and hemodialysis using a catheter. Serum albumin was higher with annual vascular access surveillance, higher BMI among women, higher urea reduction ratio, among patients in whom dialyzers were reprocessed (particularly with bleach), among dialysis units in which water purification was used, and when vascular access blood flow rates were > or =350 mL/min. Overall survival was decreased with lower albumin, creatinine, and BMI. There were interactions among albumin, age, and vintage. Whereas lower serum albumin concentrations consistently were associated with an increased risk of death, the differences were attenuated among older patients and accentuated among patients of longer vintage. CONCLUSION: Some facility-specific factors are associated with nutritional parameters including serum albumin, serum creatinine, and BMI. The associations of nutritional parameters with mortality and hospitalization vary by age, sex, and vintage but not by facility-specific factors, including those associated with the nutritional parameters themselves.

Adult↗
PubMed2004

Association of body size with outcomes among patients beginning dialysis.

BACKGROUND: Although obesity confers an increased risk of mortality in the general population, observational reports on the dialysis population have suggested that obesity is associated with improved survival. These reports have generally not examined extremely high values of body mass index (BMI; in kg/m(2)), survival >1 y, or alternative measures of adiposity. OBJECTIVE: We sought to clarify the relation between body size and outcomes among a large cohort of patients beginning dialysis. DESIGN: Data on 418 055 patients beginning dialysis between 1 April 1995 and 1 November 2000 were analyzed by using US Renal Data System data. BMI was divided into 8 categories in increments of 3 units, ranging from < 19 to > or =37, and the relation between survival and BMI was examined by using proportional hazards regression with adjustment for demographic, laboratory, and comorbidity data. RESULTS: High BMI was associated with increased survival in this cohort, even at extremely high BMI, after adjustment, and over a 2-y average follow-up time. This was true for whites, African Americans, and Hispanics but not for Asians. High BMI was also associated with a reduced risk of hospitalization and a lower rate of mortality in all mortality categories. Alternative estimates of adiposity, including the Benn index and estimated fat mass, yielded similar results, and adjustments for lean body mass did not substantially alter the findings. CONCLUSIONS: High BMI is not associated with increased mortality among patients beginning dialysis. This finding does not appear to be a function of lean body mass and, although modified by certain patient characteristics, it is a robust finding.

Body Mass Index↗
PubMed2004

The role of oxidative stress-altered lipoprotein structure and function and microinflammation on cardiovascular risk in patients with minor renal dysfunction.

Cardiovascular disease is common in patients with chronic kidney disease (CKD). As renal function fails, many patients become progressively malnourished, as evidenced by reduced levels of albumin, prealbumin, and transferrin. Malnourished patients have increased levels of C reactive protein (CRP), interleukin-6 (IL-6), and concomitant cardiovascular disease when they reach end stage. Many diseases that cause CKD, diabetes, and hypertension are also associated with cardiovascular disease. Thus the direct effect of renal failure per se directly contributing to the inflammation-malnutrition-atherosclerosis paradigm is not completely established in early stages of CKD. Some aspects of progressive renal failure, however, cause changes in plasma composition and endothelial structure and function that favor vascular injury. As renal function fails, hepatic apo A-I synthesis decreases and HDL levels fall. HDL is an important antioxidant and defends the endothelium from the effects of cytokines. Inflammation causes further structural and functional abnormalities in HDL. Apolipoprotein C III (apo C III), a competitive inhibitor of lipoprotein lipase is increased in CKD. Serum triglyceride levels increase as a result of accumulation of intermediate-density lipoprotein (IDL) comprising VLDL and chylomicron remnants. These impede vascular relaxation and are associated with cardiovascular disease. Activation of the renin angiotensin axis is a component of many renal diseases and adaptation to loss of renal mass. Angiotensin II (AngII) activates NADPH oxidases, leading to production of the superoxide anion and decreased availability of nitric oxide (NO), further impairing vascular function. H(2)O(2), produced as a consequence of superoxide dismutation, stimulates vascular cell proliferation and hypertrophy. Leukocyte-derived myeloperoxidase functions as an "NO Oxidase" in the inflamed vasculature and contributes to decreased NO bioavailability and compromised vascular reactivity. The changes in lipoprotein composition and structure as well as AngII-mediated alterations in endothelial function amplify the effect of subsequent inflammatory events.

Angiotensins↗
PubMed2004

Nephrotic livers secrete normal VLDL that acquire structural and functional defects following interaction with HDL.

BACKGROUND: Binding of very low-density lipoprotein (VLDL) isolated from serum of nephrotic rats VLDL to endothelial cells is defective. This defect is conferred on normal VLDL by prior incubation with high-density lipoprotein (HDL) from nephrotic, but not control rats. It is not known whether the defect is present in nascent VLDL (nVLDL) or is acquired after secretion. We test the hypothesis that VLDL is normal at the time of secretion from the liver and the defect in binding to endothelium is conferred following secretion through interaction with HDL. METHODS: nVLDL was synthesized by and collected from isolated perfused livers from either control or nephrotic rats. nVLDL was labeled with 3H-oleate to measure binding and 35S methionine to evaluate apolipoprotein exchange and composition. To test whether HDL conferred a binding defect, nVLDL was incubated with HDL obtained either from control or nephrotic rats prior to measurement of binding. To distinguish the effects of proteinuria from reduced albumin concentration we additionally incubated nVLDL with HDL obtained from rats with hereditary analbuminemia. Both HDL and VLDL were reisolated by centrifugation prior to subsequent binding and lipolysis determination. Exchange of 35S-labeled apolipoprotein E (apoE) among the subsequent VLDL and HDL fractions was determined. To determine the effect of HDL on lipolysis, HDL-treated VLDL was exposed to lipoprotein lipase-coated 96-well plates and 3H-oleate release measured. To establish whether differences in apoE content could explain the differences in binding and lipolysis, apoE was restored to nephrotic VLDL and lipolysis and binding were subsequently measured. RESULTS: Binding of nephrotic nVLDL was greater than control nVLDL (0.58 +/- 0.13 vs. 0.75 +/- 0.07 ng protein bound/mg cell protein) (P= 0.04, N= 6). Lipolysis was similarly elevated (0.091 +/- 0.010 vs 0.064 +/- 0.002 nmol NEFA released/well/hour) (P < 0.05). Prior incubation with nephrotic HDL reduced binding of nVLDL obtained from either nephrotic or control livers (P= 0.02, N= 6). Treatment with nephrotic (vs. control) HDL reduced both binding (control nVLDL + control HDL, 0.64 +/- 0.02; control + nephrotic, 0.43 +/- 0.06; nephrotic + control, 0.69 +/- 0.05; and nephrotic + nephrotic, 0.62 +/- 0.04 mg VLDL protein/mg cell protein) and lipolysis (control nVLDL + control HDL, 0.053 +/- 0.004; control + nephrotic, 0.038 +/- 0.004; nephrotic + control, 0.069 +/- 0.004; and nephrotic + nephrotic, 0.062 +/- 0.004 nmol NEFA/well/hour) (P < 0.05 vs. nVLDL + control HDL) of nVLDL from either source. The apoE content of nVLDL coincubated with control HDL or analbuminemic HDL was increased compared nVLDL incubated with either no HDL or nephrotic HDL (P < 0.05). Similarly, the apoE/apoA-I ratio was reduced in HDL from nephrotic rats but not in HDL from controls (P < 0.05). Reintroduction of apoE to nephrotic VLDL resulted in increased binding. CONCLUSION: Unlike circulating VLDL, binding of nVLDL from isolated livers from nephrotic rats to endothelial cells is greater and its lipolysis is increased compared to control nVLDL. Decreased binding and lipolysis is conferred following incubation with HDL isolated from control, but not nephrotic rats and binding can be restored by reintroduction of apoE. Thus both defects are conferred on VLDL by exposure to HDL obtained from nephrotic animals, possibly a consequence of a failure of nephrotic HDL to enrich VLDL with apoE during clearance.

Animals↗