Cardiovascular risk modification in participants with coronary disease screened by the Kidney Early Evaluation Program.

BACKGROUND: Coronary artery disease (CAD) identifies the need for intensive treatment of risk factors among individuals with chronic kidney disease (CKD), a high-risk, complex cardiovascular risk state. METHODS: An estimated glomerular filtration rate<60 mL/min/1.73 m2 or a urine albumin:creatinine ratio (ACR)≥30 mg/g (3.4 mg/mmol) defined CKD. RESULTS: Of 70,454 volunteers screened the mean age was 53.5±15.7 years and 68.3% were female. A total of 5410 (7.7%) had a self-reported history of CAD; 1295 (1.8%) had a history of prior percutaneous coronary intervention (PCI); and 1124 (1.6%) had a prior history of coronary artery bypass surgery (CABG). Multivariate analysis for the outcome of suboptimal CAD risk management (composite of systolic blood pressure≥130 mmHg, glucose≥125 mg/dL (6.9 mmol/L) for diabetics, total cholesterol≥200 mg/dL (5.2 mmol/L), or current smoking; n=38,746/53,403, 72.5%) revealed older age (per year) (odds ratio (OR)=1.04, 95% confidence interval (CI) 1.03-1.04, P<0.0001), male gender (OR=1.40, 95% CI 1.34-1.47, P<0.0001), ACR≥30 mg/g (3.4 mg/mmol) (OR=1.66, 95% CI 1.55-1.79, P<0.0001), body mass index (per kg/m2) (OR=1.06, 95% CI 1.06-1.06, P<0.0001), CAD without a history of revascularization (OR=1.14, 95% CI 1.02-1.28, P=0.02) and care received by a nephrologist (OR=1.49, 95% CI 1.22-1.83, P<0.0001) were associated with worse risk factor control. Prior coronary revascularization and being under the care of a cardiologist were not associated with either improved or suboptimal risk factor control. CONCLUSIONS: Chronic kidney disease is associated with overall poor rates of CAD risk factor control.

Low birth weight is associated with chronic kidney disease only in men.

The association of low birth weight and chronic kidney disease was examined in a screened volunteer population by the National Kidney Foundation's Kidney Early Evaluation Program. This is a free, community-based health program enrolling individuals aged 18 years or older with diabetes, hypertension, or a family history of kidney disease, diabetes, or hypertension. Self-reported birth weight was categorized and chronic kidney disease defined as an estimated glomerular filtration rate less than 60 ml per min per 1.73 m(2) or a urine albumin/creatinine ratio >or=30 mg/g. Among 12 364 participants, 15% reported a birth weight less than 2500 g. In men, significant corresponding odds ratios were found after adjustment for demographic characteristics and health conditions to this low birth weight and chronic kidney disease, but there was no association among women. There was no significant interaction between birth weight and race for either gender. Efforts to clinically understand the etiology of this association and potential means of prevention are essential to improving public health.

The epidemiology and control of anaemia among pre-ESRD patients with chronic kidney disease.

Anaemia is a common condition among pre-end-stage renal disease (pre-ESRD) patients with chronic kidney disease (CKD). Indeed, data from clinical studies indicate that anaemia may be present in as many as two-thirds of such patients. Use of recombinant human erythropoietin (EPO) provides an effective means of correcting anaemia in CKD patients and helps to reduce the risk of renal disease progression and related problems. Unfortunately, EPO therapy is underutilized in these persons. Consequently, anaemia remains a major problem in the pre-ESRD CKD population. Evidence suggests that anaemia in the presence of CKD can lead to an increased risk of a number of adverse outcomes, including mortality, progression of kidney disease, coronary heart disease, stroke, hospitalization, and decreases in quality of life. Anaemia's association with these adverse outcomes suggests that effective treatment of anaemia in pre-ESRD CKD patients is of great importance and that substantial efforts should be made to ensure that these patients receive appropriate therapy to correct anaemia.

Intravascular radiation therapy after balloon angioplasty of narrowed femoropopliteal arteries to prevent restenosis: results of the PARIS feasibility clinical trial.

PURPOSE: To conduct a feasibility study to assess the feasibility, safety, and outcome of endoluminal gamma radiation therapy after balloon angioplasty of superficial femoral artery (SFA) lesions. MATERIALS AND METHODS: Forty patients with claudication were enrolled in the study and underwent percutaneous transluminal angioplasty (PTA) of SFA lesions with a mean lesion length of 9.8 cm +/- 3.0 and a mean reference vessel diameter of 5.2 mm +/- 3.1. After successful PTA, a segmented centering balloon catheter was positioned to cover the PTA site. The patients were then transported to the radiation oncology suite and treated with a microSelectron HDR afterloader with use of an Ir-192 source with a prescribed dose of 14 Gy, 2 mm into the vessel wall. Ankle-brachial index (ABI) and Rutherford score were evaluated at 1, 6, and 12 months after the procedure and angiographic follow-up was conducted at 6 months. RESULTS: Radiation was delivered successfully to 35 of 40 patients. There were no procedural complications. Exercise and rest ABI were higher at 1 year (0.72 +/- 0.26 and 0.89 +/- 0.18, respectively) compared to baseline (0.51 +/- 0.25 and 0.67 +/- 0.17, respectively). Maximum walking time on a treadmill increased from 3.41 min +/- 2.41 to 4.43 min +/- 2.49 at 30 days and was 4.04 min +/- 2.8 at 12 months. The angiographic binary restenosis rate at 6 months was 17.2% and the clinical restenosis rate at 12 months was 13.3%. There were no angiographic or clinical adverse events related to the radiation therapy. CONCLUSIONS: Intraarterial radiation after PTA of SFA lesions with use of high-dose rate gamma radiation is feasible and safe. The angiographic and clinical improvements are sustainable at 1 year and represent a potent antirestenotic therapy for the treatment of narrowed peripheral arteries.

Evaluation of signals activating ubiquitin-proteasome proteolysis in a model of muscle wasting.

The ubiquitin-proteasome proteolytic system is stimulated in conditions causing muscle atrophy. Signals initiating this response in these conditions are unknown, although glucocorticoids are required but insufficient to stimulate muscle proteolysis in starvation, acidosis, and sepsis. To identify signals that activate this system, we studied acutely diabetic rats that had metabolic acidosis and increased corticosterone production. Protein degradation was increased 52% (P < 0.05), and mRNA levels encoding ubiquitin-proteasome system components, including the ubiquitin-conjugating enzyme E214k, were higher (transcription of the ubiquitin and proteasome subunit C3 genes in muscle was increased by nuclear run-off assay). In diabetic rats, prevention of acidemia by oral NaHCO3 did not eliminate muscle proteolysis. Adrenalectomy blocked accelerated proteolysis and the rise in pathway mRNAs; both responses were restored by administration of a physiological dose of glucocorticoids to adrenalectomized, diabetic rats. Finally, treating diabetic rats with insulin for >/=24 h reversed muscle proteolysis and returned pathway mRNAs to control levels. Thus acidification is not necessary for these responses, but glucocorticoids and a low insulin level in tandem activate the ubiquitin-proteasome proteolytic system.

Regulation of branched-chain ketoacid dehydrogenase flux by extracellular pH and glucocorticoids.

In muscles of rats with metabolic acidosis, branched-chain alpha-ketoacid dehydrogenase (BCKAD) activity is increased. Potential stimulatory signals include acidemia and/or glucocorticoids. It is unclear whether the signal(s) increases BCKAD activity by changing the activation state of the enzyme or by increasing the amount of enzyme. To separate the influences of extracellular pH and glucocorticoids on leucine catabolism, maximal BCKAD flux and the activation state (the ratio of basal to total flux) were measured in two cell types: 1) cells that do not express glucocorticoid receptors and 2) cells stably transfected to express glucocorticoid receptors. Acidification (pH 6.95) increased 1) the activation state from 67.2% at pH 7.4 to 82.8% at pH 6.95, 2) maximal BCKAD flux by 50%, and 3) the BCKAD subunit contents in both cell types (57, 410, and 270% for E2, E1 alpha, and E1 beta, respectively). Dexamethasone increased the BCKAD activation state from 67.2 to 82.3% in cells expressing glucocorticoid receptors, whereas dexamethasone plus acidification increased the activation state to 98%. The time course of stimulation by dexamethasone was slower than that by acidification. These results demonstrate that BCKAD is differentially regulated by extracellular pH and glucocorticoids.

Signals regulating accelerated muscle protein catabolism in uremia.

In chronic renal failure (CRF), the ATP-dependent, ubiquitin-proteasome proteolytic pathway is activated with concurrent increases in the transcription of genes encoding proteins of this pathway in muscle. We have shown that the stimuli for these responses include acidosis and glucocorticoids, but other endocrine abnormalities in CRF (e.g., insulin resistance) could contribute to these responses. In fact, a major effect of insulin in muscle is to suppress protein degradation. To examine whether insulin influences the ubiquitin-proteasome pathway, we measured protein degradation in incubated epitrochlearis muscles of diabetic and pair-fed control rats. Muscle proteolysis was increased in pathways that do not involve lysosomes or Ca(2+)-dependent proteases; but MG132, a protease inhibitor that blocks ATP synthesis, eliminated the accelerated rate of protein degradation in diabetic rat muscles. Diabetes mellitus also increased levels of mRNAs encoding ubiquitin (334%), E2 ubiquitin-conjugating enzyme (247%), and the C3 (320%), C5 (349%), and C9 (216%) proteasome subunits in muscle. Finally, transcription of the ubiquitin gene in diabetic rat muscles was increased. Diabetic rats were acidotic, but eliminating acidemia by giving NaHCO3 did not block the increase in muscle proteolysis. Giving diabetic rats insulin prevented the excessive muscle proteolysis, suggesting that insulin acts as a suppressor of the ubiquitin-proteasome pathway. Thus, the insulin resistance of uremia could contribute to muscle protein wasting in CRF.

Branched-chain amino acid catabolism in uremia: dual regulation of branched-chain alpha-ketoacid dehydrogenase by extracellular pH and glucocorticoids.

In muscles of rats with metabolic acidosis, branched-chain alpha-ketoacid dehydrogenase (BCKAD) activity is increased but the signal initiating this response is unknown. Potential signals include intracellular responses to acidemia and/or glucocorticoids. It is not known whether the signal activates BCKAD by changing the proportion of inactive (phosphorylated) or active (dephosphorylated) enzyme or increases the amount of enzyme. To separate the effects of extracellular pH and glucocorticoids on BCKAD, enzyme activity was measured in two cell types: (1) LLC-PK1 cells that do not express glucocorticoid receptors and (2) LLC-PK1-GR101 cells that express rat glucocorticoid receptors. Extracellular acidification (pH 6.95) increased the maximal BCKAD activity, the percentage of active enzyme, and the amounts of BCKAD protein. Dexamethasone also increased the percentage of active BCKAD but the time required for activation was longer than with acidification. These results demonstrate that BCKAD is dually regulated by extracellular pH and glucocorticoids.

Muscle wasting in insulinopenic rats results from activation of the ATP-dependent, ubiquitin-proteasome proteolytic pathway by a mechanism including gene transcription.

In normal subjects and diabetic patients, insulin suppresses whole body proteolysis suggesting that the loss of lean body mass and muscle wasting in insulinopenia is related to increased muscle protein degradation. To document how insulinopenia affects organ weights and to identify the pathway for accelerated proteolysis in muscle, streptozotocin-treated and vehicle-injected, pair-fed control rats were studied. The weights of liver, adipose tissue, and muscle were decreased while muscle protein degradation was increased 75% by insulinopenia. This proteolytic response was not eliminated by blocking lysosomal function and calcium-dependent proteases at 7 or 3 d after streptozotocin. When ATP synthesis in muscle was inhibited, the rates of proteolysis were reduced to the same level in insulinopenic and control rats suggesting that the ATP-dependent, ubiquitin-proteasome pathway is activated. Additional evidence for activation of this pathway in muscle includes: (a) an inhibitor of proteasome activity eliminated the increased protein degradation; (b) mRNAs encoding ubiquitin and proteasome subunits were increased two- to threefold; and (c) there was increased transcription of the ubiquitin gene. We conclude that the mechanism for muscle protein wasting in insulinopenia includes activation of the ubiquitin-proteasome pathway with increased expression of the ubiquitin gene.

Uremia-induced disturbances in hepatic carbohydrate metabolism: enhancement by sucrose feeding.

A high-sucrose (S) diet accentuates anorexia and stunts growth in uremic (U) rats, and an oral S load induces a greater hyperfructosemia in U rats than in control (C) rats. Four studies were performed to determine the roles of S feeding and an acute S load on liver carbohydrate (CHO) metabolism in U and C rats (eight to 10 rats per group). We also examined the plasma responses to either water or a S load. Levels of the main metabolites of glycolysis, gluconeogenesis, and glycogenesis were measured under basal conditions (7 hours' postmeal) in U and C rats fed either a cornstarch diet (study I) or S diet (study II) and at 30 and 60 minutes after an intragastric S load (studies III and IV) in s-fed U and C rats. The weight gain, food intake, and plasma creatinine and urea levels of the rats in the four studies were comparable. Weight gain and liver weight (g/100 g body weight) were lower in U than in C rats. In the plasma, baseline levels of lactate were decreased by uremia and S feeding and those of glucose (G) were increased by S feeding. The increases in plasma G and fructose (F) levels after a S load were greater in U rats than in C rats, whereas those of plasma lactate were comparable. In the liver under basal conditions, uremia markedly decreased levels of glycogen, F-1,6-diphosphate (F-1,6-diP), F-2,6-diP, 3-glycero-phosphate (3-glycero-P), dihydroxyacetone phosphate (DHAP), pyruvate, lactate, and adenosine triphosphate (ATP), and the phosphorylation state (ATP/adenosine diphosphate [ADP] x inorganic phosphorus [PI]), increased phosphoenolpyruvate (PEP), ADP, and Pi levels, but did not affect the cytosolic redox state (pyruvate/lactate). In addition to uremia, S feeding further decreased levels of glycogen, F-2,6-diP, 3-glycero-P, and ATP. After S loading, liver F levels increased more in U than in C rats, but glycogen and 3-glycero-P levels increased less in U than in C rats. Liver lactate and pyruvate levels increased more in U than in C rats, and the pyruvate/lactate and DHAP/3-glycero-P ratios were higher in U than in C rats after a S load. The ATP level and the phosphorylation state in U rats increased 30 minutes later in U than in C rats. Our findings indicate that uremia causes a depletion in liver glycogen, which is enhanced by S feeding and could be partially attributed to decreased glycogen synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Metabolic consequences of uremia: extending the concept of adaptive responses to protein metabolism.

An early response to metabolic acidosis is an increase in the degradation of muscle protein to provide the nitrogen needed to increase glutamine production so the kidney can excrete acid. In patients with renal insufficiency, this process may represent an example of a trade-off adaptation to uremia. It requires a hormone (glucocorticoids) and the metabolic response is maladaptive because the inability of the damaged kidney to maintain acid-base balance results in loss of muscle protein. Studies of cultured cells and rats and humans with normal kidneys demonstrate that acidosis stimulates the degradation of both amino acids and protein, which would block the normal adaptive responses to a low-protein diet (ie, to reduce the degradation of essential amino acids and protein). Evidence from studies in rats and humans with chronic uremia show that acidosis is a major stimulus for catabolism. The mechanism includes stimulation of specific pathways for the degradation of protein and amino acids. Since other catabolic conditions (eg, starvation) appear to stimulate the same pathways, understanding the mechanism in acidosis could be applicable to other conditions. Thus, the loss of lean body mass in uremia appears to be a consequence of a normal metabolic response that persists until acidosis is corrected.

Mechanisms that cause protein and amino acid catabolism in uremia.

Anorexia and/or a protein- and calorie-restricted diet can cause protein wasting by limiting the intake of essential amino acids (EAA) and, hence, protein synthesis. By this mechanism plus the effects of inadequate calories, restricted diets could contribute to the loss of lean body mass of uremic patients. Uremia also impairs the normal metabolic responses that must be activated to preserve body protein, thereby augmenting the adverse effects of anorexia. The responses impaired are those that conserve EAA and protein, which results in catabolism of EAA and muscle protein. An important factor that initiates abnormal adaptive responses in uremia is metabolic acidosis, because acidosis stimulates muscle protein degradation and increases the activity of branched-chain ketoacid dehydrogenase and, hence, the catabolism of branched-chain amino acids (BCAA). The effects of acidosis could be mediated by impaired regulation of intracellular pH and/or an increase in glucocorticoid production. Research directed at identifying the specific proteolytic pathways that are activated by metabolic acidosis has excluded a major role for Ca(2+)-activated or lysosomal proteases and suggests activation of an adenosine triphosphate (ATP)- and ubiquitin-dependent proteolytic pathway. The mechanism of activation of this pathway includes an increase in mRNA for enzymes involved in protein and amino acid catabolism.

Influence of ammonia and pH on protein and amino acid metabolism in LLC-PK1 cells.

Metabolic acidosis inhibits protein synthesis (PS) and stimulates protein degradation (PD) in muscle and cultured myocytes but causes hypertrophy of the proximal tubule. The reason for this tissue-specific difference in response to acidosis is unknown, but it might be related to stimulation of renal ammonia production since ammonia reportedly increases PS and inhibits PD in cultured kidney cells. We examined how ammonia and pH could interact to change protein turnover in confluent LLC-PK1 cells. Varying extracellular pH from 6.95 to 7.60 did not alter PS or PD even though intracellular pH changed predictably. Six millimolar NH4Cl did not change PS while 20 mM inhibited PS; there was no interaction with pH. This unexpected difference from the reported stimulation of PS by NH4Cl could be explained by our use of L-[U-14C]phenylalanine rather than radiolabelled leucine to measure PS. NH4Cl was found to inhibit leucine degradation which would increase radiolabelled leucine available for incorporation into protein. Either 6 mM or 20 mM NH4Cl inhibited PD measured as the release of L-[14C]phenylalanine from prelabelled protein. Experiments with an inhibitor of lysosomal function, chloroquine, suggest that NH4Cl inhibits lysosomal proteolysis. There was no interaction of cell pH and ammonia-induced changes in PD. Thus, the response of renal cells to acidification differs markedly from myocytes and ammonia changes protein turnover primarily by suppressing PD.

Effect of glucocorticoids and extracellular pH on protein metabolism in cultured cells.

Chronic renal failure (CRF) is complicated by metabolic acidosis and muscle wasting. Protein degradation (PD) in skeletal muscle is accelerated in rats with CRF and correction of uremic acidosis returns PD to normal. Experimentally induced acidosis in normal rats accelerates PD and requires an intact adrenal axis. To investigate mechanisms of pH-induced changes in protein metabolism, BC3Hl myocytes and LLC-PK1 renal epithelial cells were studied. Low extracellular pH increases PD in myocytes but does not change PD in LLC-PK1 cells. In both types of cells, intracellular pH changes predictably as extracellular pH is varied. Exogenous glucocorticoids (GC) do not alter PD in either cell line, but inhibit protein synthesis in BC3Hl myocytes. Since extracellular pH stimulates PD only in BC3Hl myocytes and since LLC-PK1 cells may not possess GC receptors, we can compare and contrast the effects of pH and GC on protein metabolism to study the role of GC in acid-stimulated proteolysis.

Contribution of experimental studies on the nutritional management of children with chronic renal failure.

A few of the many reports of experimental chronic renal failure have been summarized. Anorexia and food selection have been studied in experimental uremia and the findings are comparable with those observed in uraemic children. The optimal dietary protein content for growth is close to the minimal requirement for "optimal" growth. Protein excess leads to growth retardation and renal deterioration in uraemic rats, at least with the commonly used dry diets. The increased water requirement may be more critical for growth than the blood urea level or acidosis, although this requires further investigation. Reduction of the dietary protein by 50% and supplementation with essential amino acids (EAA) results in growth similar to that of the 100% protein diet. There is no growth improvement despite low blood urea levels, but the renal parenchymal is preserved. Supplementation with nitrogen-free analogues is more frequently associated with defective growth; the optimal mixture remains to be defined, and to date, when nutrition is identical, nitrogen-free analogues offer no benefit for renal preservation compared with EAA. Sucrose-rich diets have adverse effects on uraemia. These effects are associated with fructose intolerance and with reduced energy storage in the liver. The precise metabolic alteration remains to be defined.

Trace elements and lipid peroxidation abnormalities in patients with chronic renal failure.

Plasma selenium (Se), zinc (Zn) and copper (Cu) levels and antioxidant metalloenzymes, glutathione peroxidase (GPX) and superoxide dismutase (SOD), were studied in 17 patients on maintenance hemodialysis (HD) (group I), 14 uremic patients (group II) and 14 healthy subjects (group III). Plasma Se levels and erythrocyte GPX were significantly lower in the HD group (for Se: 0.69 +/- 0.12 vs. 1.05 +/- 0.13 mumol/l in controls; for erythrocyte GPX: 34.4 +/- 6.4 vs. 49.2 +/- 9 IU/g hemoglobin in controls) and a significant correlation was found between the two parameters (r = 0.66, p less than 0.005). There was also a correlation between decreased plasma Zn and erythrocyte SOD activity (r = 0.58, p less than 0.02) and between decreased plasma Cu and erythrocyte SOD (r = 0.60, p less than 0.02). Plasma malondialdehyde levels were augmented in HD patients (5.08 +/- 0.26 vs. 2.55 +/- 0.15 mumol/l in controls and 2.79 +/- 0.40 mumol/l in the uremic group). The catalase activity was increased in HD patients (202 +/- 24 vs. 140 +/- 40 IU/mg hemoglobin in group III). A defective antioxidant activity may thus contribute to increased peroxidative damage to cells in the course of dialysis.

[Enoxaparin in the prevention of thrombosis of extracorporeal circulation during dialysis of patients with chronic renal failure]. / L'enoxaparine dans la prévention de la thrombose du circuit extracorporel de dialyse des insuffisants rénaux chroniques.

Chronic renal failure patients under haemodialysis are exposed to two dangers: haemorrhage and clotting of the extracorporeal circulation circuit. This problem can be solved by using low molecular weight heparins. Two studies were conducted to evaluate the effectiveness and safety of a low molecular weight heparin: enoxaparin. The first study, which involved 42 chronic renal failure patients under haemodialysis without any particular risk, enabled the optimum dosage (1 mg/kg bodyweight) to be determined. The second study, which concerned 46 patients at high risk of haemorrhage who received enoxaparin 0.5 mg/kg or 0.75 mg/kg depending on the vascular approach, confirmed that enoxaparin was highly effective (clotting of the extracorporeal circuit in only 0.6 p. 100 of the cases) and well tolerated (bleeding in only 0.2 p. 100 of the cases).

[The use of enoxaparine for anticoagulation in extracorporeal circulation in hemodialysis at high risk for hemorrhage]. / Utilisation de l'énoxaparine pour l'anticoagulation du circuit extracorporel des hémodialyses à haut risque hémorragique.

After evaluation of efficacy of a low molecular weight heparin (LMWH), enoxaparine (Lovenox), in patients on continuous hemodialysis without a particular known hemorrhagic risk, this same LMWH was administered during 493 dialysis sessions to 46 patients presenting various degrees of risk of hemorrhage. Lower doses of 0.5 mg/kg or 0.75 mg/kg as bolus injections were administered at the start of the 4 or 5 hourly session. Clotting in the extracorporeal circulation (ECC) was noted in 0.6% treatments, the product being effective in all other sessions. Only one case of bleeding can be imputed to the LMWH injected during hemodialysis (0.2% of sessions). Although an open trial, the superiority of enoxaparine both for antithrombotic activity in ECC, and its simple management, as well as the small number of hemorrhages noted, has led to the routine use of this method in all patients at hemorrhagic risk.

[Biological activity of enoxaprine (PK 10169) in hemodialysis. A dose study]. / Activités biologiques de l'éjnoxaparine (PK 10,169) en hémodialyse. Etude de dose.

Anti-Xa and anti-IIa activity were evaluated in 42 patients with chronic renal insufficiency, in an open randomized trial, to determine optimal dose of PK 10169 for prevention of coagulation in extracorporeal circuit during hemodialysis sessions. PK 10169 was given as single doses of 0.75, 1 and 1.25 mg/kg at start of dialysis, into the arterial line. All dialysis sessions were continued over the 4 hours provided for without the need for further injections. A linear relation existed between anti-Xa and anti-IIa activity measured at end of dialysis and the dose injected (p less than 0.001). Efficacy and tolerance were assessed clinically and biologically and were rated excellent at the 3 dose levels, the best tolerance/efficacy ratio being at the 1 mg/kg dosage.