Lipoprotein metabolism in chronic renal insufficiency

Chronic renal insufficiency (CRI) is associated with a characteristic dyslipidemia. Findings in children with CRI largely parallel those in adults. Moderate hypertriglyceridemia, increased triglyceride-rich lipoproteins (TRL) and reduced high-density lipoproteins (HDL) are the most usual findings, whereas total and low-density lipoprotein cholesterol (LDL-C) remain normal or modestly increased. Qualitative abnormalities in lipoproteins are common, including small dense LDL, oxidized LDL, and cholesterol-enriched TRL. Measures of lipoprotein lipase and hepatic lipase activity are reduced, and concentrations of apolipoprotein C-III are markedly elevated. Still an active area of research, major pathophysiological mechanisms leading to the dyslipidemia of CRI include insulin resistance and nonnephrotic proteinuria. Sources of variability in the severity of this dyslipidemia include the degree of renal impairment and the modality of dialysis. The benefits of maintaining normal body weight and physical activity extend to those with CRI. In addition to multiple hypolipidemic pharmaceuticals, fish oils are also effective as a triglyceride-lowering agent, and the phosphorous binding agent sevelamer also lowers LDL-C. Emerging classes of hypolipidemic agents and drugs affecting sensitivity to insulin may impact future treatment. Unfortunately, cardiovascular benefit has not been convincingly demonstrated by any trial designed to study adults or children with renal disease. Therefore, it is not possible at this time to endorse general recommendations for the use of any agent to treat dyslipidemia in children with chronic kidney disease.     

Endothelium-dependent vasodilation and oxidative stress in chronic renal failure: impact on cardiovascular disease

Despite significant progress in renal replacement therapy, the mortality from cardiovascular disease (CVD) in patients with chronic renal failure (CRF) is many times higher than in the general population. The traditional risk factors are frequently present in CRF patients. However, based upon conventional risk factor analysis, these factors do not fully explain the extraordinary increase in morbidity and mortality in CVD among patients with CRF. Accumulating evidence suggests that CRF is associated with impaired endothelial cell function. In recent years, the role of endothelial dysfunction (ED) and excessive oxidative stress (OS) in the development of CVD has been highlighted. ED is an early feature of vascular disease in different diseases such diabetes, hypertension, hypercholesterolemia, and coronary heart disease. The precise mechanism which induces ED is not clear. Several factors however, including OS-related accumulation of uremic toxins, hypertension and shear stress, dyslipidemia with cytotoxic lipoprotein species such as small, dense low-density lipoprotein (LDL) particles, competitive inhibition of endothelial nitric oxide (NO) by increased production by asymmetrical dimethylarginine (ADMA) are pathogenic. In addition, it is known that excessive OS causes ED. An overproduction of reactive oxygen species (ROS) may injure the endothelial cell membrane, inactivate NO, and cause oxidation of an essential cofactor of nitric oxide synthase (NOS). Recent studies have demonstrated that an impaired endothelium-dependent vasodilation and OS are closely related to each other in patients with CRF.     

Lipid Metabolism in Uremia: Effect of Regular Hemofiltration and Hemodialysis Treatment

Plasma triglycerides and cholesterol were measured in controls, non-dialyzed patients with chronic renal insufficiency and uremic patients receiving either regular hemodialysis or hemofiltration treatment. Normal and elevated cholesterol levels remained generally unaffected by chronic hemodialysis and hemofiltration as well. Whereas long-term hemodialysis even up to 59 months (home-dialysis) was unable to improve hypertriglyceridemia, patients undergoing regular hemofiltration showed a prolonged decrease in plasma triglycerides. In one case, excessive hypertriglyceridemia still existing after five years of chronic hemodialysis could be normalized by hemofiltration.     

Nitric oxide in uremia: effects of several potentially toxic guanidino compounds

Vascular and neurologic impairment remain an important source of morbidity in patients with chronic renal failure (CRF). A portion of CRF patients still suffers from uremic encephalopathy or other signs of nervous system impairment. Several reports demonstrate increased incidence of cardiac infarction and cerebrovascular accidents in CRF patients, even in those with otherwise adequate dialysis treatment [1]. Premature vascular disease, including myocardial infarction, stroke, and peripheral vascular disorder, are the leading causes of death in this population. Although several traditional risk factors for vascular disease and endothelial dysfunction, including smoking, diabetes, dyslipidemia, and hypertension, are often increased in CRF, these factors can only partly explain the high vasculopathy-related morbidity and mortality. Several authors have postulated that CRF-associated atherosclerosis and endothelial dysfunction result from accumulation of certain 'uremic factors,' the identities of which are still a matter of debate. These factors include a variety of guanidino compounds (GCs), which have been shown to be nitric oxide synthase (NOS) modulators both in vitro and in vivo. However, other effects of accumulated uremic GCs have been identified.     

Effect of protein-restricted diet on serum lipids and atherosclerosis risk factors in patients with chronic renal failure

Early changes in lipid metabolism and appearance of atherosclerosis risk factors play a key role in the development of cardiovascular disease of chronic renal failure (CRF). In the effort to evaluate the effects of protein restricted diet on dyslipidemia, we studied 122 patients with CRF (S-creatinine 1.3-9 mg/dl); 58.2% of whom were on antihypertensive drugs treatment. Patients had been separated into 6 groups: group 1 was kept on a free diet; groups 2, 3, 4, 5, 6 were kept on a protein-restricted diet from 12, 24, 36, 48, 60 months, respectively. We found hypertriglyceridemia, pathologic levels of esterified cholesterol in high density lipoprotein (HDL-C) and pathologic apolipoprotein A1/B ratio in group 1; the comparison with other groups--whose values were normal range after 12, 24 months of treatment--showed significant differences. The lipidic parameters were independent of the duration of CRF and of patients' age. Serum creatinine showed a significant correlation with tryglicerides and HDL-C values only in group 1. Total cholesterol and apolipoprotein B were significantly greater in hypertensives than in normotensives. In our opinion, a moderate restriction in protein intake could be effective in preventing and in halting the early alterations of lipid metabolism in CRF.     

Growth hormone and the kidney: the use of recombinant human growth hormone (rhGH) in growth-retarded children with chronic renal insufficiency.

Hypothalamic production of growth hormone releasing hormone stimulates the anterior pituitary gland to release growth hormone (GH). The clinical manifestations of GH on tissues are either direct or are mediated by insulin-like growth factors (IGF). Both the somatic effects of GH and the renal manifestations of an increase in glomerular filtration rate and renal plasma flow are mediated by IGF. The increase in glomerular filtration rate/renal plasma flow that occurs with either exogenous or endogenous GH is not apparent in patients with chronic renal failure (CRF); therefore, it is unlikely that recombinant human growth hormone (rhGH) treatment of patients with CRF will result in glomerular hyperfiltration. Longitudinal studies are required to determine if the glomerulosclerosis and renal functional impairment occurring in GH and growth hormone releasing hormone transgenic mice occurs after rhGH treatment of growth-retarded uremic rats with GH resulted in an improvement in growth velocity. This led to preliminary studies in growth-retarded children with CRF by using rhGH. The acceleration of growth velocity was dramatic despite the fact that GH levels are elevated in uremia. The elevated IGF carrier proteins in uremic children may contribute to the growth retardation. Treatment with rhGH may be efficacious by stimulating a net increase in the free (unbound) IGF levels. Hyposecretion of GH may contribute to the failure to achieve optimal growth after successful renal transplantation. Treatment with rhGH may be efficacious in improving the growth velocity of renal allograft recipients.     

Serum apolipoprotein profile of patients with chronic renal failure

Serum concentrations of apolipoproteins A-I, A-II, B, C-I, C-II, C-III and E were determined by electroimmunoassay in 56 patients with chronic renal failure (CRF) in the predialytic phase. The results were compared with those obtained in asymptomatic normolipidemic subjects, patients with type IV hyperlipoproteinemia, and patients with type II diabetes mellitus. CRF patients had reduced concentrations of ApoA-I and ApoA-II, normal levels of ApoB and ApoC-I, and increased concentrations of ApoC-II and, in particular, of ApoC-III. There was a significant reduction in the levels of ApoE, especially in male patients. In comparison with type IV, hyperlipoproteinemic patients, CRF patients had lower concentrations of ApoA-I, ApoA-II, ApoB, ApoC-I and, particularly, ApoE; there was no difference in ApoC-III levels reflecting the hypertriglyceridemia common to both disorders. Similar but less marked differences were also found in comparison with type II diabetics. The findings suggest that in CRF, the accumulation of ApoC-III-enriched lipoprotein particles accompanied by a moderate hypertriglyceridemia may be caused more probably by an impaired catabolism than overproduction of triglyceride-rich lipoproteins. CRF patients with vascular disease tended to have higher serum concentrations of triglycerides, cholesterol and ApoB and lower ApoA-I/ApoC-III and ApoA-I/ApoB ratios than patients without vascular disease.     

Comparative effects of cerivastatin and fenofibrate on the atherogenic lipoprotein phenotype in proteinuric renal disease

Patients with nephrotic-range proteinuria have impaired clearance of triglyceride-rich lipoproteins. This results in the atherogenic lipoprotein phenotype (mild hypertriglyceridemia, low high-density lipoproteins [HDL], and excess small, dense low-density lipoproteins [LDLIII]). Excess remnant lipoproteins (RLP) are linked to hypertriglyceridemia and may contribute to the atherogenicity of nephrotic dyslipidemia. A randomized crossover study compared the effects of a statin (cerivastatin) and a fibrate (fenofibrate) on LDLIII and RLP in 12 patients with nephrotic-range proteinuria. Cerivastatin reduced cholesterol (21%, P: < 0.01), triglyceride (14%, P: < 0.05), LDL cholesterol (LDL-C; 23%, P: < 0.01), total LDL (18%, P: < 0.01), and LDLIII concentration (27% P: < 0.01). %LDLIII, RLP-C, and RLP triglyceride (RLP-TG) were unchanged. Plasma LDLIII reduction with cerivastatin treatment correlated with LDL-C reduction (r(2) = 34%, P: < 0.05). Fenofibrate lowered cholesterol (19%), triglyceride (41%), very low-density lipoprotein cholesterol (52%), LDLIII concentration (49%), RLP-C (35%), and RLP-TG (44%; all P: < 0.01). Fenofibrate also reduced %LDLIII from 60 to 33% (P: < 0.01). HDL-C (19%, P: < 0.01) increased with fenofibrate treatment; LDL-C and total LDL were unchanged. The reduction in LDLIII concentration and RLP-C with fenofibrate treatment correlated with plasma triglyceride reduction (LDLIII r(2) = 67%, P: < 0.001; RLP cholesterol r(2) = 58%, P: < 0.005). Serum creatinine increased with fenofibrate treatment (14%, P: < 0.01); however, creatinine clearance was unchanged. LDLIII concentration was 187 +/- 85 mg/dl after cerivastatin treatment and 133 +/- 95 mg/dl after fenofibrate treatment. Cerivastatin and fenofibrate reduce LDLIII concentration in nephrotic-range proteinuria. However, atherogenic concentrations of LDLIII remain prevalent after either treatment. Fenofibrate but not cerivastatin reduces remnant lipoproteins. The two treatments seem to reduce LDLIII by different mechanisms, suggesting a potential role for combination therapy to optimize lowering of LDLIII and RLP.     

Down-regulation of hepatic lecithin:cholesterol acyltransferase gene expression in chronic renal failure

BACKGROUND: Chronic renal failure (CRF) is associated with premature arteriosclerosis, impaired high-density lipoprotein (HDL) maturation, increased pre-beta HDL (a lipid-poor HDL species), reduced HDL/total cholesterol ratio, hypertriglyceridemia, and depressed lipolytic activity. The latter has been, in part, attributed to elevated pre-beta HDL, which is a potent inhibitor of lipoprotein lipase (LPL). Accumulation of cholesterol in the arterial wall is a critical step in atherogenesis, and HDL-mediated cholesterol removal from peripheral tissues mitigates atherosclerosis. Lecithin:cholesterol acyltransferase (LCAT) is essential for maturation of HDL and cholesterol removal by HDL from peripheral tissues. Earlier studies have revealed depressed plasma LCAT enzymatic activity in patients with CRF. This study was conducted to determine whether impaired LCAT activity can be confirmed in CRF animals and if so whether it is due to down-regulation of hepatic LCAT expression. METHODS: Hepatic tissue LCAT mRNA and plasma LCAT enzymatic activity were measured in male Sprague-Dawley rats six weeks after excisional 5/6 nephrectomy or sham operation. RESULTS: Compared with the controls, the CRF group exhibited a significant reduction of hepatic tissue LCAT mRNA abundance. The reduction in hepatic LCAT mRNA was accompanied by a marked reduction of plasma LCAT activity and elevation of serum-free cholesterol in the CRF animals. LCAT activity correlated positively with the HDL/total cholesterol ratio and inversely with free cholesterol and triglyceride concentrations. CONCLUSIONS: CRF leads to a marked down-regulation of hepatic LCAT mRNA expression and plasma LCAT activity. This abnormality can impair HDL-mediated cholesterol uptake from the vascular tissue and contribute to cardiovascular disease. In addition, LCAT deficiency can, in part, account for elevated serum-free cholesterol, reduced HDL/total cholesterol, and elevated pre-beta HDL in CRF. The latter can, in turn, depress lipolytic activity and hinder triglyceride-rich lipoprotein clearance in CRF.     

Autoantibodies against oxidized LDL in chronic renal failure: role of renal function, diet, and lipids

Lipid peroxidation (LP) has recently been suggested to trigger the atherosclerotic process as well as to worsen the progression of renal disease. Autoantibodies against oxidized low-density lipoproteins (Ox-LDLAb) were considered to provide a sensitive marker to detect LDL oxidation in vivo. To date few studies have been reported on Ox-LDLAb levels in patients with different degrees of renal failure. The aim of this study was to evaluate the influences of renal function, dietary manipulation, and lipids on Ox-LDLAb concentrations in uremic patients either on conservative or replacement therapy. Seventy-one patients (42 males, 29 females) aged 60 +/- 19 years with chronic renal failure (CRF) of different etiology and degree were divided into four groups according to serum creatinine levels [sCr(mg/dl)] and diet: CRF I > or = 1.5-3.0, CRF II > 3.0-5.5, and CRF III > 5.5 were all patients on a conventional low-protein diet, while a fourth group included patients on a vegetarian diet supplemented with keto analogues and amino acids (CRF SD >3.0). A further group was represented by patients on dialysis therapy. All patients were examined for Ox-LDLAb, triglycerides (TG), total cholesterol, HDL and LDL cholesterol, and apolipoproteins Apo A1, Apo B, and Lp(a). The results were compared with those of 20 controls (9 males and 11 females) aged 52 +/- 11 years with sCr <1.5 mg/dl. Ox-LDLAb increased, although not significantly, with TG and Lp(a) from the early stages of CRF along with the deterioration of renal function. However, TG and Lp(a) levels were significantly higher in all groups of patients except those on vegetarian diet (CRF SD). This group also showed the lowest Ox-LDLAb levels. No relationship was observed between lipids or apolipoproteins and Ox-LDLAb. Hyperlipidemic patients did not show higher Ox-LDLAb levels than normolipidemics. Our results show a progressive increase of LP as the renal function declines, which may account for the increased risk of cardiovascular disease reported in uremia. Dialysis does not correct significantly the oxidative state observed in patients with end-stage renal disease. Vegan diet, by reducing LP, TG, and Lp(a), is supposed to decrease the risk of cardiovascular disease and worth being reconsidered as an alternative effective therapeutic tool in patients with advanced CRF.     

Increased erythrocyte phosphatidylserine exposure in chronic renal failure.

The appearance of phosphatidylserine, an aminophospholipid normally confined to the inner monolayer, at the outer leaflet of red cell membrane may have several pathophysiologic implications. This study examines erythrocyte phosphatidylserine exposure in chronic renal failure (CRF) patients on conservative treatment or on dialysis, to assess possible alterations to phospholipid asymmetry in a condition associated with a state of deranged red cell function. A significant increase in phosphatidylserine-expressing erythrocytes was found in undialyzed patients with CRF (2.32%) and patients on hemodialysis (3.06%) and on peritoneal dialysis (2.14%) compared with control subjects (0.68%). In undialyzed CRF patients, a strong correlation (r = 0.903) was found between the percentage of phosphatidylserine-expressing red cells and the serum creatinine concentration. The increased exposure of phosphatidylserine in uremic erythrocytes may be due to inhibition of phosphatidylserine transport from the outer to the inner leaflet of plasma membrane and may promote an increased erythrophagocytosis. In reconstitution experiments, normal erythrocytes showed an increase in phosphatidylserine-expressing cells when incubated in uremic plasma (3.2% after 2 h versus 1.1% at beginning of incubation), whereas phosphatidylserine-positive uremic erythrocytes decreased when resuspended in normal plasma (2.03% after 2 h and 1.65% after 8 h versus 2.9% at beginning of incubation). Preliminary characterization of the putative uremic compound(s) indicates a molecular weight between 10,000 and 20,000, as well as heat instability. These findings show an impairment of erythrocyte membrane phospholipid asymmetry in CRF patients, regardless of the dialysis treatment. Such abnormality seems related to the uremic state and could contribute to the red cell pathology present in CRF.     

Clinical assessment and management of dyslipidemia in patients with chronic kidney disease

Chronic kidney disease (CKD) is a common cause of cardiovascular disease (CVD). Several factors contribute to the onset and progression of atherosclerosis and CVD in CKD patients. Most of the cases of coronary heart disease in the general population can be explained by traditional risk factors, whereas non-traditional risk factors, including oxidative stress, anemia, inflammation, malnutrition, vascular calcification, and endothelial dysfunction, have been proposed to play a central role in the pathogenesis of CVD in CKD patients. However, the precise mechanism of CVD initiation in CKD patients remains unclear. Lipid-lowering therapies may decrease proteinuria, and increase or maintain renal function. Because the serum levels of triglyceride-rich lipoproteins are increased in CKD patients, particularly in advanced stages, the serum non-HDL cholesterol level may be a better biomarker of dyslipidemia than the serum LDL cholesterol level in this population. A meta-analysis showed that statin therapy was associated with decreased albuminuria in comparison with a placebo. Moreover, lipid-lowering therapy with statins is effective in reducing the risk of CVD in the early stages of CKD, whereas the benefit of statins in patients with end-stage renal disease may be limited.     

Accelerated atherosclerosis, dyslipidemia, and oxidative stress in end-stage renal disease

Premature atherosclerosis is a major cause of morbidity and mortality in end-stage renal disease patients. Dyslipidemia and increased oxidative stress contribute to premature atherogenesis in these patients. The dyslipidemia of end-stage renal disease consists of both quantitative and qualitative abnormalities in serum lipoproteins. Qualitative changes include hypertriglyceridemia (increased remnant lipoproteins), low high-density lipoprotein-cholesterol, and increased lipoprotein (a). In addition to quantitative changes, lipoproteins in end-stage renal disease undergo compositional and qualitative changes that make them pro-atherogenic, such as various modifications of apolipoprotein B, including oxidation, and modification by advanced glycation end-products. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and low-dose fibrates could be effective therapies for lipid disorders. The best evidence for increased oxidative stress in end-stage renal disease is the demonstration of increased plasma F2-isoprostanes. Confirmation of the positive findings with high-dose alpha-tocopherol in the Secondary Prevention with Antioxidants of Cardiovascular Disease in End-stage Renal Disease Study is urgently needed. Clinical trials with statins and other drugs that improve dyslipidemia also need to be undertaken. These therapies could clearly lead to a reduction in cardiovascular morbidity and mortality in these patients.     

Serum Lipids and Lipoproteins in Schizophrenic Patients with Normal Renal Function Treated with Hemodialysis

To study the effect of hemodialysis on serum lipids and lipoproteins, five patients with normal renal function who had undergone hemodialysis for schizophrenic symptoms for 10 weeks in a crossover study were investigated. Active or sham (no dialysate flow through the filter) dialysis was instituted randomly. Serum lipids were isolated by ultracentrifugation and precipitation before and after each period. High density lipoprotein (HDL) cholesterol levels were constantly low and correlated negatively with serum alkaline phosphatase concentrations (p less than 0.05). Serum and very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol increased during active, and to a lesser extent during sham, dialysis. Dialysis of this intensity does not affect HDL. The low levels may be secondary to subclinical cholestasis from neuroleptic drug treatment. Some individuals may develop hypertriglyceridemia of unknown pathogenesis during hemodialysis. Both these lipoprotein abnormalities are risk factors for the development of atherosclerosis.     

Lipoprotein abnormalities in hyperlipidemic and normolipidemic men on hemodialysis with chronic renal failure.

Lipids, lipoproteins, apolipoproteins (apo) and apo E polymorphism were determined in 101 men with chronic renal failure (CRF) were were on hemodialysis and 101 healthy controls matched for age and sex. Patients with CRF on hemodialysis had significantly higher levels of serum triglycerides, very-low-density lipoprotein (VLDL) cholesterol, intermediate-density lipoproteins (IDL), and lower levels of low- and high-density lipoproteins (LDL and HDL, respectively) than controls. Regarding apolipoproteins, serum apo B concentrations were decreased. Apo C-III concentrations in sera and in VLDL and HDL fractions were significantly increased in 35 hemodialysis patients compared with 32 controls. Seventy-eight of the 101 CRF patients had normal serum cholesterol and triglycerides (less than 5.2 mmol/liter and less than 2.3 mmol/liter, respectively). However, this subgroup also showed a significant increase in VLDL-triglycerides and serum apo E concentration in addition to changes observed in the group as a whole. Apo E polymorphism in our study population did not differ from that reported for other European populations. According to the different apo E phenotypes, lipids and lipoprotein composition showed no significant differences in controls or patients. We conclude that accumulation of triglyceride-rich lipoproteins in patients with CRF on hemodialysis may thus be at least in part related to the enrichment of apo C-III in VLDL and HDL fractions. Lipoprotein profile in hemodialysis patients, including those with normal serum cholesterol and triglyceride levels, is consistent with high cardiovascular risk.     

Abnormal lipoprotein metabolism in diabetic nephropathy

It is well known that patients with diabetes have a high incidence of cardiovascular disease (CVD), and the incidence of CVD becomes substantially elevated with development of diabetic nephropathy. The mechanisms for dyslipidemia in diabetic nephropathy are multifactorial and complex. Long-term hyperglycemia causes generalized vascular endothelial damage, which reduces functional lipoprotein lipase, leading to increased triglyceride (TG) levels and decreased high-density lipoprotein cholesterol (HDL-C). In overt-diabetic nephropathy, hypoproteinemia markedly increases low-density lipoprotein cholesterol (LDL-C), and renal failure specifically increases remnant lipoproteins and decreases HDL-C and LDL-C. Overt diabetic nephropathy exhibits remarkable postprandial hypertriglyceridemia with hyper-apolipoprotein (apo) B48, a marker of chylomicron and its remnants. Apo CIII is a key inhibitor of lipolysis and particle uptake of TG-rich lipoproteins, which is specifically increased in advanced chronic kidney disease, irrespective of the presence of diabetes. LDL size becomes smaller with advanced stages of diabetic nephropathy, whereas LDL size is not reduced in hemodialysis patients (HD). HD patients have marked lower levels of HDL3-C than controls. HD patients also have substantially low apo AI and high serum amyloid A (SAA) levels, suggesting the replacement of apo AI by SAA is stimulated in HDL particles.     

Cardiovascular risk factors in predialysis patients: baseline data from the Chronic Renal Impairment in Birmingham (CRIB) study

BACKGROUND: Patients with end-stage kidney failure have a greatly increased risk of developing premature cardiac and vascular disease. However, little is known about the evolution of cardiovascular diseases in individuals with less severely impaired kidney function. METHODS: The prevalence of cardiovascular diseases and of suspected cardiovascular risk factors was studied in a group of 369 individuals (median age, 63 years, 67% male) with various degrees of impaired kidney function (calculated creatinine clearances 6 to 105 mL/min), in 103 patients with angiographically proven coronary artery disease, and in 103 apparently healthy individuals. These patients are being followed prospectively. RESULTS: Of those patients with kidney disease, 34% had a history of vascular disease and 21% had left ventricular hypertrophy on electrocardiogram at baseline. Traditional risk factors were prevalent, with a history of hypertension in 76% of kidney disease patients, diabetes in 15%, and dyslipidemia with reduced low-density lipoprotein (LDL) cholesterol, elevated serum triglycerides, and decreased high-density lipoprotein (HDL) levels. Other possible cardiovascular risk factors include elevated concentrations of plasma homocysteine, as well as low serum albumin and hemoglobin levels. Patients with more severely impaired renal function had lower diastolic blood pressures, lower LDL and HDL cholesterol levels, were more anemic, and had higher plasma homocysteine concentrations. CONCLUSIONS: Vascular disease and left ventricular hypertrophy are prevalent among patients with chronic kidney disease not requiring dialysis. In addition to traditional risk factors, other features of the uremic syndrome such as anemia, hyperhomocysteinemia, and inflammation (suggested by hypoalbuminemia) may contribute.     

Inflammation and coronary calcification in renal patients--factors that may explain increased cardiovascular risk, and poorer results of coronary interventions?

Cardiovascular disease (CVD) is one of the major causes of mortality in patients with renal diseases, with increased odds ratio of mortality with risk factors as diverse as cholesterol, vascular stiffness, chronic inflammation and hyperhomocysteinemia. Several factors have been incriminated to explain the increase in coronary vascular calcification (CVC) in this particular population. Increased duration of dialysis, dyslipidemia, altered calcium-phosphorus metabolism, and chronic inflammation have all been associated with increased CVC. We present here four case reports illustrating the differences in the pathophysiology, therapy and prognosis of calcific coronary heart disease seen in uremic patients.     

Plasma and Lp(a)-associated PAF-acetylhydrolase activity in uremic patients undergoing different dialysis procedures

Plasma and Lp(a)-associated PAF-acetylhydrolase activity in uremic patients undergoing different dialysis procedures. BACKGROUND: Platelet-activating factor (PAF) is a potent inflammatory mediator associated with several physiopathological conditions, including renal diseases. PAF is degraded to the inactive metabolite lyso-PAF by PAF-acetylhydrolase (PAF-AH), which is considered as a potent anti-inflammatory and anti-atherogenic enzyme associated with lipoproteins. In this study, we evaluated the plasma- and lipoprotein(a) [Lp(a)]-associated PAF-AH activity in relationship to plasma lipid parameters and Lp(a) isoform size in patients with mild/moderate chronic renal failure (CRF), as well as in hemodialysis (HD) and chronic ambulatory peritoneal dialysis (CAPD) patients. METHODS: We studied 74 patients undergoing maintenance HD, 44 patients undergoing CAPD, 56 patients with mild/moderate CRF, and 98 healthy subjects whose lipid profile, as well as plasma and high-density lipoprotein (HDL)-associated PAF-AH activity, was determined. Moreover, the effect of Lp(a) plasma levels on the distribution of PAF-AH among plasma lipoproteins, as well as the specific activity and kinetic properties of PAF-AH on two different Lp(a) isoforms, was measured in each studied group. RESULTS: The plasma PAF-AH activity in all studied groups was significantly higher than in controls, and the increase was more profound in CAPD patients. The HDL-associated PAF-AH activity, expressed per milliliter of plasma, was similar among all studied groups; however, when it was expressed as either per milligrams of HDL cholesterol or per milligrams of plasma apolipoprotein (apo) AI, the PAF-AH activity was significantly higher in all patient groups compared with controls. All patient groups had significantly elevated plasma Lp(a) levels, which altered the distribution of PAF-AH among the plasma lipoproteins compared with that observed in subjects with very low plasma Lp(a) levels (<8 mg/dl). Additionally, in each studied group, the specific activity as well as the apparent Km and Vmax values of the 19K4 apo(a) isoform were significantly higher (P < 0.01) compared with the values of the 23K4 isoform. However, the specific activity, as well as the Km and Vmax values on either the 19K4 apo(a) isoform or the 23K4 isoform, was significantly higher in CAPD patients compared with the other three groups. CONCLUSIONS: Plasma PAF-AH activity is increased in uremic patients. This elevation is more profound in CAPD patients, who also exhibit a more atherogenic lipid profile and more pronounced alterations in the specific activity and the kinetic constants of Lp(a)-associated PAF-AH.     

Chronic renal failure accelerates atherogenesis in apolipoprotein E-deficient mice

Cardiovascular mortality is 10 to 20 times increased in patients with chronic renal failure (CRF). Risk factors for atherosclerosis are abundant in patients with CRF. However, the pathogenesis of cardiovascular disease in CRF remains to be elucidated. The effect of CRF on the development of atherosclerosis in apolipoprotein E-deficient male mice was examined. Seven-week-old mice underwent 5/6 nephrectomy (CRF, n = 28), unilateral nephrectomy (UNX, n = 24), or no surgery (n = 23). Twenty-two weeks later, CRF mice showed increased aortic plaque area fraction (0.266 +/- 0.033 versus 0.045 +/- 0.006; P < 0.001), aortic cholesterol content (535 +/- 62 versus 100 +/- 9 nmol/cm(2) intimal surface area; P < 0.001), and aortic root plaque area (205,296 +/- 22,098 versus 143,662 +/- 13,302 micro m(2); P < 0.05) as compared with no-surgery mice; UNX mice showed intermediate values. The plaques from uremic mice contained CD11b-positive macrophages and showed strong staining for nitrotyrosine. Systolic BP and plasma homocysteine concentrations were similar in uremic and nonuremic mice. Plasma urea and cholesterol concentrations were elevated 2.6-fold (P < 0.001) and 1.5-fold (P < 0.001) in CRF compared with no-surgery mice. Both variables correlated with aortic plaque area fraction (r(2) = 0.5, P < 0.001 and r(2) = 0.3, P < 0.001, respectively) and with each other (r(2) = 0.5, P < 0.001). On multiple linear regression analysis, only plasma urea was a significant predictor of aortic plaque area fraction. In conclusion, the present findings suggest that uremia markedly accelerates atherogenesis in apolipoprotein E-deficient mice. This effect could not be fully explained by changes in BP, plasma homocysteine levels, or total plasma cholesterol concentrations. Thus, the CRF apolipoprotein E-deficient mouse is a new model for studying the pathogenesis of accelerated atherosclerosis in uremia.