Reduced Creatinine Clearance Research Articles

The profile of cardiac patients with renal artery stenosis

ObjectivesWe examined the prevalence and severity of renal artery stenosis (RAS) in patients undergoing cardiac catheterization who were deemed at risk for RAS based on clinical or laboratory criteria for study entry, but who had not previously been suspected of having RAS. BackgroundThe diagnosis of atherosclerotic RAS remains problematic because its clinical manifestations are nonspecific. MethodsConsecutive patients undergoing non-emergent cardiac catheterization at a single institution during a 12-month period were evaluated using standardized clinical, laboratory, and angiographic criteria. Patients exhibiting at least one of four predefined selection criteria (severe hypertension, unexplained renal dysfunction, acute pulmonary edema with hypertension, or severe atherosclerosis) were prospectively registered and underwent coincident diagnostic renal angiography. ResultsRenal angiography was performed in 851 patients and was diagnostic in 837. Angiographically evident renal atherosclerosis was present in 39% of the population, with RAS ≥50% in 120 (14.3%) and severe stenosis (≥70%) in 61 (7.3%). Severe stenosis was present in 48 (7%) patients with severe atherosclerosis, 38 (16%) with renal dysfunction, 25 (9%) with hypertension, and 2 (22%) with acute pulmonary edema with hypertension. The prevalence was higher in those exhibiting multiple selection criteria. In a multivariate model, severe RAS was associated with age, female gender, reduced creatinine clearance, increased systolic blood pressure, and peripheral or carotid artery disease. ConclusionsIn a population at risk of, but not previously suspected of having RAS, severe RAS is associated with simple and readily determined clinical and laboratory patient characteristics. These data facilitate focused application of diagnostic renal angiography.

Effects of nonsteroidal anti-inflammatory drugs on postoperative renal function in adults with normal renal function.

Nonsteroidal anti-inflammatory drugs (NSAIDs) can play a major role in the management of acute pain in the peri-operative period. However, there are conflicting views on whether NSAIDs are associated with adverse renal effects. The primary objective of this review was to determine the effects of NSAIDs on postoperative renal function in adults with normal preoperative renal function. Electronic searches for relevant randomised and quasi-randomised controlled trials in Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE were performed. Attempts were also made to identify trials from citation lists of relevant trials, review articles and clinical practice guidelines. Handsearching of conference abstracts published in major anaesthetic journals was also performed. (Search date: 7 February 2003) The inclusion criteria were randomised or quasi-randomised comparisons of individual NSAIDs with either each other or placebo for treatment of postoperative pain, with relevant postoperative renal outcome measures, in adult surgical patients with normal renal function. The data was extracted independently by two reviewers. The primary outcome measure was creatinine clearance within the first two days after surgery. Secondary outcome measures included serum creatinine, urine volume, urinary sodium level, urinary potassium level, fractional excretion of sodium, fractional excretion of potassium, need for dialysis and need for diuretic or dopamine treatment for renal insufficiency. Weighted mean differences for continuous outcomes and relative risk for dichotomous outcomes were estimated. Nineteen trials ( n = 1204) fulfilled the selection criteria for this review. NSAIDs reduced creatinine clearance by 16 ml/min (95%CI 5 to 28) and potassium output by 38 mmol/day (95%CI 19 to 56) on the first day after surgery compared to placebo. There was no significant difference in serum creatinine on the first day (0 umol/L, 95%CI -5 to 4) compared to placebo. No significant reduction in urine volume during the early postoperative period was found. There was no significant difference in serum creatinine in the early postoperative period between patients receiving diclofenace and ketorolac (or indomethacin). No cases of postoperative renal failure requiring dialysis were described. The trials were homogeneous for the primary outcome. NSAIDs caused a clinically unimportant transient reduction in renal function in the early postoperative period in patients with normal preoperative renal function. NSAIDs should not be withheld from adults with normal preoperative renal function because of concerns about postoperative renal impairment.

Downregulation of hepatic acyl-CoA:diglycerol acyltransferase in chronic renal failure

Chronic renal failure (CRF) is associated with hypertriglyceridemia and elevated plasma VLDL and IDL concentrations. These events can be due to either increased production or depressed catabolism of triglyceride-rich lipoproteins. Several studies have documented downregulation of lipoprotein lipase, hepatic triglyceride lipase, and the VLDL receptor, leading to depressed clearance and elevated plasma concentration of triglyceride-rich lipoproteins and their remnants in CRF. However, the effect of CRF on the triglyceride biosynthetic pathway has not been explored. Diglycerol acyltransferase (DGAT) is a microsomal enzyme that joins acyl-CoA to 1,2 diacylglycerol and, as such, constitutes the final step in triglyceride biosynthesis. Two distinct forms of DGAT (DGAT-1 and -2) have thus far been identified. The present study was undertaken to examine the effect of CRF on DGAT gene expression and activity in the liver, which is the source of endogenous triglycerides in the circulation. Male Sprague-Dawley rats were studied 8 wk after 5/6 nephrectomy (CRF) or sham operation. DGAT-1 and DGAT-2 mRNA abundance and DGAT activity were quantified. The CRF group showed reduced creatinine clearance, elevated plasma triglycerides, and VLDL concentrations. This was accompanied by significant reductions in hepatic DGAT-2 mRNA abundance (P < 0.01) and total DGAT activity (P < 0.1), pointing to diminished hepatic triglyceride production capacity in CRF animals. In conclusion, CRF results in significant downregulation of hepatic DGAT gene expression and activity. Given the critical role of DGAT in triglyceride biosynthesis, the present study points to diminished, not increased, hepatic triglyceride synthetic capacity in CRF rats.

Creatinine clearance and signs of end-organ damage in primary hypertension.

A reduction in renal function is associated with high cardiovascular morbidity and mortality in hypertension. The aim of the present study was to investigate the relationship between creatinine clearance and subclinical organ damage in 957 never previously treated, middle-aged patients with primary hypertension. Renal function was estimated by means of the serum creatinine level using the Cockcroft-Gault formula; left ventricular hypertrophy (LVH) was determined according to electrocardiographic criteria; and retinal vascular changes were evaluated by direct ophthalmoscopy. Creatinine clearance was, on the average, 83+/-21.2 ml/min, and the prevalence of LVH and retinopathy was 13 and 49%, respectively. Creatinine clearance was inversely related to the duration of disease (r=-0.132, P<0.0001), systolic blood pressure (r=-0.110, P=0.001), serum glucose (r=-0.090, P=0.007), total cholesterol (r=-0.196, P<0.0001), and LDL-cholesterol (r=-0.196, P<0.0001). Patients in the lower quintile of creatinine clearance showed a higher prevalence of electrocardiogram (ECG) determined LVH (P=0.04), as well as retinal changes (P=0.02). The risk of having LVH or retinal vascular changes increases significantly with each s.d. decrease in creatinine clearance, regardless of traditional cardiovascular risk factors. Moreover, patients with ECG-determined LVH and retinal changes showed lower creatinine clearance as compared to those with lesser degrees of target organ involvement (P<0.01). In conclusion, a mild reduction in creatinine clearance is associated with preclinical end-organ damage in patients with normal creatinine and primary hypertension. These data may help explain the high cardiovascular mortality observed in patients with renal dysfunction. Routine evaluation of creatinine clearance could be useful for identifying patients at higher cardiovascular risk.

Renal Function, Peak Anti‐Xa Levels and Enoxaparin Dosing

Background: Low molecular weight heparin is administered in a fixed, weight‐adjusted dose without laboratory monitoring in the majority of patients. However, there is still uncertainty regarding optimum dosing in patients with renal impairment.Aim: To examine the association between peak anti‐Xa levels and creatinine clearance in patients treated with enoxaparin.Method: Prospective study of hospitalised patients receiving enoxaparin 1 mg/kg twice daily. Peak anti‐Xa levels were measured after patients received at least 3 doses of SC enoxaparin and were compared in 3 patient groups according to baseline creatinine clearance (Group 1: Crcl ≤ 30 rnUmin; Group 2: Crcl &lt; 30 and ≤ 60 mL/min; Group 3: Crcl &lt; 60 mL/min).Results: 50 patients were studied (54% male). Peak anti‐Xa levels after a mean of 5.2 doses of enoxaparin were within or above the recommended therapeutic range (0.6‐1.0 unit per mL) in 96% of patients ( 48/50). At this time, five of the seven patients (71.4%) in Group 1 had peak anti‐Xa levels &lt; 1.0 unit per mL, compared with 15/19 (78.9%) in Group 2 and 7/24 (29.2%) in Group 3. Mean peak anti‐Xa levels were 1.58 ± 0.54 unit per mL, 1.25 ± 0.38 unit per mL and 0.93 ± 0.28 unit per mL in Groups 1, 2 and 3 respectively, p = 0.001.Conclusion: Patients with reduced creatinine clearance who were receiving enoxaparin 1 mg/kg twice daily achieved significantly higher peak anti‐Xa levels compared with those with normal creatinine clearance. Dose reduction and/or routine laboratory monitoring of enoxaparin should be considered in patients with impaired renal function.

Reduced hemoglobin after heart transplantation is no independent risk factor for survival but is associated closely with impaired renal function.

Reduced hemoglobin (Hb) levels after heart transplantation (HTX) are common; however, there are only limited data on the association of posttransplant anemia with survival. In the present study, the effect of Hb levels determined 7 to 12 months after HTX on survival was investigated in 156 heart transplant recipients (129 men and 27 women; age at transplantation, 51.3+/-10.45 years; follow-up, 6.77+/-3.6 years) by univariate and multivariate analyses including a broad range of clinical and demographic patient characteristics. Anemia by standard definition was found in 141 of 156 (91.6%) patients. According to Hb levels above or below the gender-specific median (men, 12.07 g/dL; women, 11.69 g/dL), patients were separated into a high- or low-Hb group, respectively. Kaplan-Meier analysis demonstrated significantly worse survival in the low-Hb group (P =0.033). Those patients showed significantly lower body weight, higher serum creatinine levels, and lower calculated creatinine clearance; the association of creatinine clearance and Hb levels was highly significant (P <0.0001). No differences were demonstrated between groups for age, preoperative cardiac diagnosis, diabetes, azathioprine, steroid or angiotensin-converting enzyme inhibitor medication, leukocyte and thrombocyte levels, rejection index, or cytomegalovirus (CMV) infection or serostatus. Multivariate Cox stepwise regression analysis demonstrated that CMV infection, diabetes, and female donor gender were significant risk factors for post-HTX survival. An Hb level below the median was, however, completely lost as a risk factor (P =0.44); instead, a strong trend for reduced creatinine clearance could be demonstrated (P =0.09). Subsequently, a significant association was demonstrated between low calculated creatinine clearance and impaired survival by separate Kaplan-Meier analysis (P =0.02). Low Hb levels after HTX do not represent an independent risk factor for reduced survival, but the demonstrated correlation appears to be primarily caused by concomitant functional renal impairment. Further studies will be required to investigate the role of post-HTX anemia as a sensitive indicator of functional renal impairment and the effects of anemia treatment on long-term survival.

Arterial stiffness and kidney function.

The vascular hallmark of subjects with end-stage renal disease undergoing hemodialysis is increased aortic stiffness, a phenomenon independent of mean arterial blood pressure, wall stress, and standard cardiovascular risk factors such as plasma glucose, cholesterol, obesity, and smoking. These observations suggest that subtle links might associate arterial stiffness and kidney function in normotensive and hypertensive populations. Recently, aortic pulse wave velocity and creatinine clearance have been shown to be statistically associated in subjects with plasma creatinine < or =130 micromol/L, again independently of mean arterial blood pressure and classical cardiovascular risk factors. This association was even shown to predominate in subjects younger than age 55 years. In addition, acceleration of aortic pulse wave velocity with age was more important in these subjects than in untreated normotensive control individuals, and the phenomenon was consistently predicted by baseline plasma creatinine values. Among all antihypertensive drugs, angiotensin-converting enzyme inhibitors only were shown to exhibit a significant and independent effect on aortic stiffness. The use of these drugs was significantly associated with improvement of large aortic stiffness in subjects treated for hypertension. In conclusion, increased stiffness of central arteries is independently associated with reduced creatinine clearance in subjects with mild to severe renal insufficiency, indicating that kidney diseases may interact not only with small but also with large conduit arteries, independently of age, blood pressure level, and classical cardiovascular risk factors. Whether sodium, divalent ionic species (calcium, phosphates), and the renin-angiotensin-aldosterone system play a role in such alterations remains to be elucidated.

Coagulation, inflammation and myocardial dysfunction in unstable coronary artery disease and the influence of glycoprotein IIb/IIIa inhibition and low molecular weight heparin

Patients with unstable coronary artery disease (CAD) have an increased risk of subsequent myocardial infarction and death. This study evaluated the safety and efficacy of treatment with glycoprotein IIb/IIIa inhibition in addition to aspirin, low molecular- weight heparin and its influence on coagulation and inflammation. Also, early and differentiated risk assessment utilising markers of inflammation, myocardial damage and dysfunction were evaluated.The Global Utilisation of Strategies To open Occluded arteries-IV (GUSTO-IV) trial randomised 7800 patients with unstable CAD to 24 or 48 hours infusion of abciximab or placebo in addition to routine treatment with aspirin and heparin or dalteparin. Baseline levels of creatinine, C-reactive protein (CRP), troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-proBNP) were analysed. At selected sites, all patients received subcutaneous dalteparin (n=974), in stead of heparin infusion (n=6826). In a sub-population of dalteparin treated patients (n=404), serial measurements of markers of coagulation, fibrinolysis and inflammation were also performed. Addition of abciximab to dalteparin as the primary treatment of unstable CAD was not associated with any significant reduction in cardiac events but a doubled risk of bleedings. The combination of abciximab with dalteparin seemed as safe when used with heparin. Despite full dose dalteparin and aspirin there was a simultaneous activation of the inflammation, coagulation and fibrinolysis systems without any influence of the abciximab treatment. Elevated levels of CRP, TnT, and NT-proBNP and reduced creatinine clearance were independently related to short and long-term mortality. The best prediction of high and low risk was provided by a combination of NT-proBNP and creatinine clearance. Any detectable elevation of TnT and reduced creatinine clearance, but neither elevation of CRP nor NT-proBNP, were also independently associated to a raised risk of subsequent myocardial infarction.Abbreviations: Acute coronary syndrome (ACS), Brain natriuretic peptide (BNP), Coefficient of variance(CV), Coronary artery disease (CAD), Coronary artery bypass grafting (CABG), Creatine kinase-MB (CK-MB), C-reactive protein (CRP), Electrocardiogram (ECG), Glycoprotein IIb/IIIa (GPIIb/IIIa), Global Utilisation of Strategies To Open Occluded Arteries IV (GUSTO-IV), Interleukin-6(Il-6), Low-molecular weight heparin (LMWH), N-terminal pro-Brain natriuretic peptide (NT-proBNP),Myocardial infarction (MI), Percutaneous coronary intervention (PCI), Plasminogen activator(tPA), Plasminogen activator inhibitor (PAI-1), Soluble fibrin (SF), Thrombin-antithrombin complex(TAT), Troponin T (TnT), Unfractionated heparin (UFH).

Chronotoxicity of Nedaplatin in Rats

Chronotoxicologic profiles of nedaplatin, a platinum compound, were evaluated in rats maintained under a 12 light/12 dark cycle with light from 07:00 h to 19:00 h. Nedaplatin (5 mg/kg) was injected intravenously, once a week for 5 weeks at 08:00 h or 20:00 h. The suppression of body weight gain and reduction of creatinine clearance were significantly greater with the 20:00 h than 08:00 h treatment. Accumulation of nedaplatin in the renal cortex and bone marrow were also greater with 20:00 h treatment. There were significant relationships between the nedaplatin content in the kidney and bone marrow and degree of injury to each. These results suggest that the nedaplatin-induced toxicity depends on its dosing-time, and it is greater with treatment at 20:00 h, during the active phase. The dosing-time dependency in the accumulation of nedaplatin in the tissue of the organs might be involved in this chronotoxicologic phenomenon.

Analysis of arterial pressure regulating systems in renal post-transplantation hypertension

To investigate if blood volume expansion, increased sodium retention, changes in neurohumoral arterial pressure control, or altered extrarenal resistance vessel function contribute to the development of renal post-transplantation hypertension. F1-hybrids (F1H) obtained from crossing spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats received either an SHR or an F1H kidney graft. Groups consisted of 8-12 animals and were investigated between days 1 and 14 after renal transplantation in three sets of experiments including arterial pressure recordings, plasma volume measurements, metabolic studies, and small vessel myography. Two days after completion of bilateral nephrectomy, arterial pressure was elevated by 15-20 mmHg in recipients of an SHR kidney, compared with syngeneically transplanted controls. There was no evidence for increased sodium and fluid retention during the early development of renal post-transplantation hypertension despite a 35% reduced creatinine clearance in recipients of an SHR kidney. The plasma renin-angiotensin-aldosterone system was similarly suppressed in both recipients of an SHR kidney and controls. The arterial pressure response to ganglionic blockade did not differ between groups and there was no evidence for changes in extrarenal resistance vessel function, which could be involved in the genesis of this form of hypertension. None of the investigated mechanisms was altered in a way that might help to explain the rapid and consistent development of hypertension in recipients of an SHR kidney. We conclude that post-transplantation hypertension in recipients of an SHR kidney is due to mechanisms other than those investigated in the present study.

Protein restriction and AST-120 improve lipoprotein lipase and VLDL receptor in focal glomerulosclerosis

Imai rats exhibit spontaneous focal glomerulosclerosis (FGS) with progressive proteinuria and hyperlipidemia leading to renal insufficiency by age 34 weeks. Recently, we reported marked down-regulations of skeletal muscle and adipose tissue lipoprotein lipase (LPL) and very low-density lipoprotein (VLDL) receptor in male Imai rats at 32 weeks of age. Dietary protein restriction and oral adsorbent AST-120 (AST) have been shown to slow progression of renal disease and attenuate hyperlipidemia in the Imai rats. This study tested the hypothesis that amelioration of proteinuria by protein restriction or use of oral adsorbent AST-120 beginning at 10 weeks of age may improve renal disease and LPL and VLDL receptor deficiencies in Imai rats. Ten-week-old male Imai rats were randomly assigned to those fed either a regular diet, low protein diet (LPD), or regular diet containing the adsorbent preparation, AST-120. Ten-week-old male Sprague-Dawley rats served as controls. The animals were observed for 24 weeks. Six rats were included in each group. All diets were prepared in powder form. The untreated 34-week-old Imai rats showed severe proteinuria, hypoalbuminemia, 50% reduction in creatinine clearance, hypercholesterolemia, hypertriglyceridemia, and elevated plasma VLDL concentration. This was associated with significant reductions in plasma post-heparin LPL activity, hepatic lipase activity, as well as adipose tissue and skeletal muscle immunodetectable LPL and VLDL receptor proteins. Protein restriction mitigated the decline in creatinine clearance, ameliorated proteinuria, hypoalbuminemia, hypertension, and hypercholesterolemia, lowered plasma VLDL, and improved plasma postheparin LPL activity, hepatic lipase activity, LPL, and VLDL receptor proteins in skeletal muscle and adipose tissue. Similar improvements were observed in all parameters with AST administration. Moderate protein restriction and use of oral adsorbent can slow progression of renal disease and, thereby, ameliorate LPL, hepatic lipase, and VLDL receptor deficiencies and the associated hyperlipidemia in rats with spontaneous FGS.

Cholesterol and the risk of renal dysfunction in apparently healthy men.

Despite extensive knowledge about abnormal lipid patterns in patients with end-stage renal disease, the association between cholesterol and the development of renal dysfunction is unclear. We evaluated this association in a prospective cohort study among 4,483 initially healthy men participating in the Physicians' Health Study who provided blood samples in 1982 and 1996. Main outcome measures were elevated creatinine, defined as >/= 1.5 mg/dl (133 micromol/L), and reduced estimated creatinine clearance, defined as </=55 ml/min. Cholesterol parameters included total cholesterol (<200, 200 to 239, and >/= 240 mg/dl), HDL (<40 or >/= 40 mg/dl), total non-HDL cholesterol, and the ratio of total cholesterol to HDL. We used logistic regression to calculate age- and multivariable adjusted odds ratios as a measure for the relative risk. After 14 yr, 134 men (3.0%) had elevated creatinine and 244 (5.4%) had reduced creatinine clearance. The multivariable relative risk for elevated creatinine was 1.77 (95% confidence interval [CI], 1.10 to 2.86) for total cholesterol >/= 240 mg/dl, 2.16 (95% CI, 1.42 to 3.27) for HDL <40 mg/dl, 2.34 (95% CI, 1.34 to 4.07) for the highest quartile of total cholesterol/HDL ratio (>/= >6.8), and 2.16 (95% CI, 1.22 to 3.80) for the highest quartile of non-HDL cholesterol (>/= 196.1). Similar although smaller associations were observed between cholesterol parameters and reduced creatinine clearance. Elevated total cholesterol, high non-HDL cholesterol, a high ratio of total cholesterol/HDL, and low HDL in particular were significantly associated with an increased risk of developing renal dysfunction in men with an initial creatinine <1.5 mg/dl.

Mild renal dysfunction and subclinical cardiovascular damage in primary hypertension.

The presence of mild renal dysfunction is associated with high cardiovascular morbidity and mortality rates in patients with primary hypertension. The pathophysiological mechanisms underlying this association are currently unknown. We investigated the relation between mild renal dysfunction and subclinical cardiovascular organ damage in 358 never previously treated patients with primary hypertension. Mild renal dysfunction was defined as a creatinine clearance <60 mL/min and/or the presence of microalbuminuria. Left ventricular mass index and carotid intima-media thickness were assessed by ultrasound scan. The prevalence of mild renal dysfunction, left ventricular hypertrophy, and carotid plaque was 18%, 48%, and 28%, respectively. Mild renal dysfunction was related to the presence of several risk factors, such as older age, higher blood pressure levels and lipid status, and smoking habits. Patients with the highest left ventricular mass and carotid intima-media thickness (upper quartiles) showed a higher prevalence of mild renal dysfunction (P<0.0001). After adjusting for duration of hypertension, mean blood pressure, smoking habits, and age, we found that the risk of left ventricular hypertrophy and/or carotid atherosclerosis increased by 43% with each SD reduction in creatinine clearance, and by 89% with each SD increase in albuminuria. Mild renal dysfunction is associated with preclinical end-organ damage in patients with primary hypertension. These data may help explain the high cardiovascular mortality rates reported in patients with low glomerular filtration rate or with increased albuminuria. The evaluation of creatinine clearance and urinary albumin excretion could be useful for identifying subjects at higher cardiovascular risk.

Mildly reduced creatinine clearance is associated with coronary artery disease in women: The NHLBI-sponsored WISE study

Mildly reduced creatinine clearance is associated with coronary artery disease in women: The NHLBI-sponsored WISE study

Effect of Sodium Alterations on Hepatic Cytochrome P450 3A2 and 2C11 and Renal Function in Rats

Numerous dietary supplements are known to modulate cytochrome P450 (CYP)-mediated metabolism and subsequently alter drug toxicity or efficacy in animals and humans. In the present study we investigated the effect of varying amounts of sodium intake on renal function and the metabolic activity of the hepatic CYP3A2 and CYP2C11 isoforms. Rats were maintained on standard rodent chow or a low-salt rice diet. Within each of these groups rats received either a single intraperitoneal injection of furosemide to initiate salt depletion, or saline. Additional groups included salt supplementation of 500 mg/300 g body weight/day and 1.25 g/300 g body weight/day of sodium chloride solution. Rats receiving the low-salt diet, both with and without a concomitant furosemide administration, had a significant reduction in creatinine clearance without changes in serum creatinine. In addition, urine flow rate was markedly reduced in rats maintained on the low-salt diet. Western blot analysis indicated that neither sodium supplementation nor deprivation altered hepatic microsomal CYP3A2 levels; however, hepatic CYP2C11 levels significantly increased in rats receiving the largest sodium supplement. In vitro metabolic activity of CYP3A2 was unchanged as compared with controls. Activity of CYP2C11 was significantly reduced in both rat groups receiving additional sodium supplements. Acute manipulation of daily sodium intake does alter renal function and specific hepatic CYP isoforms and should be considered when using these rat models.

Upregulation of acyl-CoA: cholesterol acyltransferase in chronic renal failure.

Chronic renal failure (CRF) is associated with profound abnormalities of lipid metabolism and accelerated arteriosclerotic cardiovascular disease. In a recent study, we found marked downregulation of hepatic lecithin-cholesterol acyltransferase, or LCAT, expression, which can account for impaired HDL maturation and depressed HDL cholesterol concentration in CRF. Here, we report on the effect of CRF on acyl-CoA:cholesterol acyltransferase (ACAT) expression. ACAT is an intracellular enzyme that catalyzes esterification of free cholesterol to cholesterol ester for storage or secretion. ACAT plays a major role in hepatic production and release of VLDL, intestinal absorption of cholesterol, foam cell formation, and atherogenesis. We examined hepatic expression of ACAT-1 and ACAT-2 mRNA (Northern blot) and protein (Western blot) abundance and total ACAT activity in male CRF rats (6 wk after 5/6 nephrectomy) and sham-operated controls. The CRF animals showed a significant reduction in creatinine clearance, marked hypertriglyceridemia, modest hypercholesterolemia, and significant upregulation of hepatic tissue ACAT-2 protein and mRNA abundance. In contrast, hepatic ACAT-1 mRNA and protein abundance were unaffected by CRF. Upregulation of ACAT-2 expression was accompanied by a significant increase in hepatic ACAT activity and a significant decrease in hepatic microsomal and whole liver free cholesterol concentration. Thus CRF results in significant upregulation of hepatic ACAT-2 (but not ACAT-1) expression and ACAT activity, which may, in part, contribute to the associated lipid disorders.

Treatment of recurrent hepatitis B infection in liver transplant recipients.

1. Therapeutic decisions are guided by a patient's clinical status (severity of disease and presence of comorbidities) and previous drug-exposure history. 2. Lamivudine is safe and effective in liver transplant recipients with recurrent hepatitis B virus (HBV) infection caused by wild-type virus or failure of hepatitis B immunoglobulin therapy. Lamivudine resistance, developing in approximately 25% after 12 months of therapy, is its main limitation. 3. Famciclovir is safe in liver transplant recipients; however, virological and clinical responses are less consistent than with lamivudine. Thus, lamivudine is favored over famciclovir as first-line therapy in transplant recipients with no previous exposure to nucleoside analogues. 4. Although limited in availability, adefovir dipivoxil appears safe and effective in treating liver transplant recipients with lamivudine-resistant HBV disease. Close monitoring of renal function is recommended, with dose adjustment in patients with reduced creatinine clearances. 5. Limited data suggest that intravenous ganciclovir, tenofovir disoproxil fumarate, and interferon alfa may be useful as rescue therapies for patients with lamivudine- or famciclovir-resistant HBV disease. 6. Antiviral therapy with two or more suitable agents may minimize the chance for viral resistance; therefore, future therapeutic strategies likely will use combination therapy in the long-term management of recurrent HBV disease.

Interleukin-6 Stimulates Tubular Regeneration in Rats with Glycerol-Induced Acute Renal Failure

Interleukin-6 stimulates tubular regeneration in rats with glycerol-induced acute renal failure. Background: Interleukin 6 (IL-6) is a pleiotropic cytokine released after endotoxemia, trauma and organ injury. IL-6 may act in cellular proliferation activating transduction signals and Ras/Map cascade or the HGF/c-met axis. We tested the effect of IL-6 in the regeneration of tubular epithelia after acute tubular necrosis (ATN) in rats. Methods: Rats with glycerol-induced acute renal failure (Gly-ARF) were treated with IL-6 200 µg/kg/day. Functional, histological and immunohistochemical tests were done 24 and 72 h after Gly-ARF to localise mitotic cells (BrdU). The renal expression of c-met (Western-Blot) and circulating levels of HGF (ELISA) were also determined. Results: Rats with Gly-ARF had reduced creatinine clearance that was not influenced by IL-6. The histological appearance of ATN was also unaffected by IL-6. The IL-6 treated rats showed a significant increase in tubular cell proliferation in cortex and medulla, as well as in the expression of c-met protein in the renal cortex, compared to untreated Gly-ARF rats. The plasma HGF concentration was equally elevated in treated and untreated Gly-ARF rats. Discussion: IL-6 stimulates tubular regeneration after Gly-ARF and increases the expression of c-met in the renal cortex. Gly-ARF rats have high circulating levels of HGF that is targeted to act in the injured kidneys by the IL-6 overexpressed renal c-met.

Coronary revascularization: A procedure in transition from on-pump to off-pump? The role of glucose-insulin-potassium revisited in a randomized, placebo-controlled study

Objective: To investigate an optimized glucose-insulin-potassium (GIK) solution regimen as an alternate myocardial protective strategy in off-pump coronary artery bypass graft (OP-CAB) surgery and as a supplement to conventional coronary artery bypass graft (CABG) surgery using cardiopulmonary bypass (CPB). Design: Prospective, randomized, placebo-controlled. Setting: Single institution, cardiothoracic specialty hospital. Participants: Forty-four patients scheduled for elective multivessel coronary artery surgery using either conventional CPB (n = 22) or OP-CAB techniques (n = 22). Interventions: Preischemic, ischemic, and postischemic administration of GIK solution was carried out, optimally dosed to ensure nonesterified fatty acid (NEFA) suppression, and supplemented with magnesium, a glycolytic enzymatic cofactor. Measurements and Main Results: GIK solution therapy reduced plasma NEFA levels (p < 0.001) in OP-CAB surgery and CPB groups but failed to affect the incidence of non–Q wave perioperative myocardial infarction, incidence of postoperative atrial fibrillation, incidence of postoperative infection, reduction in creatinine clearance, or duration of postoperative intensive care unit or hospital length of stay. After adjusting for GIK solution therapy, OP-CAB surgery resulted in significantly less ischemic injury (troponin I >15 μg/L, 19.0% v 91.3%; p = 0.0001) and reduced postoperative infections (14.3% v 43.5%; p = 0.049). Conclusion: GIK solution therapy achieved NEFA suppression and an insignificant trend toward reduced biochemical parameters of ischemic injury in OP-CAB surgery and CPB groups, but no major clinical benefit (perioperative myocardial infarction, intensive care unit length of stay, or hospital length of stay) was shown after elective CABG surgery in low-risk patients. Compared with CPB, OP-CAB surgery significantly reduced ischemic injury and postoperative infections. Copyright 2002, Elsevier Science (USA). All rights reserved.

Reduced nitric oxide synthase activity in rats with chronic renal disease due to glomerulonephritis

Animal studies with systemic nitric oxide synthase (NOS) inhibition and renal ablation, suggest that NO deficiency is both a cause and a consequence of chronic renal disease (CRD). This study examined a glomerulonephritis (GN) model of CRD to determine if NO is deficient. In addition to measuring indices of renal function (proteinuria, creatinine clearance, structural damage), indices of total and renal nitric oxide production also were assessed (total NO(X) excretion, renal NOS activity, renal NOS protein abundance, plasma levels of NOS substrate and endogenous inhibitor). Rats developed increasing proteinuria 12 to 20 weeks after induction of GN (with anti-glomerular basement membrane, GBM, antibody) and at 20 weeks exhibited reduced creatinine clearances and increased glomerulosclerosis relative to age-matched controls. Total NO(X) excretion was reduced and the renal cortical NOS activity and neuronal NOS (nNOS) abundance was decreased relative to controls. There was no impact on renal or aortic endothelial NOS expression or cerebellar nNOS. The plasma l-arginine (Arg) concentration was well maintained but plasma asymmetric dimethylarginine (ADMA) concentration increased in GN versus control animals. Total and renal NOS activity is reduced in the GN model of CRD due to increased circulating endogenous NOS inhibitors and decreased renal nNOS abundance.