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Biomedical subjects

W F Keane

Publications and source records attributed to W F Keane.

At least 73 records · Page 4Linked to original sources
PubMed1995

Human mesangial cell production of monocyte chemoattractant protein-1: modulation by lovastatin.

Macrophages play a critical role in the progression of clinical and experimental glomerular injury. Serum-stimulated human fetal mesangial cells in culture produce a chemotactic factor that is monocyte-selective. This chemotactic factor is most likely monocyte chemoattractant protein-1 (MCP-1) as a monoclonal antibody directed against MCP-1, but not an irrelevant antibody, suppressed the mesangial cell-derived chemotactic activity. Inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase by lovastatin resulted in a reduction of the mesangial cell-derived chemotactic activity as well as MCP-1 mRNA expression. The inhibitory effects of lovastatin in the presence of exogenous cholesterol were reversed by mevalonate, suggesting a role for isoprenoid intermediates of the mevalonate pathway and/or isoprenylated proteins in mesangial cell MCP-1 regulation. These findings suggest an additional mechanism by which HMG-CoA reductase inhibition in vivo may reduce glomerular injury.

Cells, Cultured↗
PubMed1995

The angiotensin II receptor antagonist losartan reduces blood pressure but not renal injury in obese Zucker rats.

Agents that interfere with the renin-angiotensin system (RAS) may ameliorate progressive renal injury, particularly in a setting where intrarenal RAS activity appears to be elevated. Whether RAS antagonists affect renal disease progression when intrarenal RAS activity is not increased is unclear. In this study, therefore, the effects of the angiotensin II receptor antagonist losartan on glomerular and tubulointerstitial injury were investigated in obese Zucker rats (OZR), an experimental model of progressive renal disease characterized by reduced intrarenal renin content and reduced plasma renin activity. Losartan (100 or 200 mg/L of drinking water) was administered to OZR beginning at 26 wk of age, when renal disease was established. At 38 and 44 wk of age, losartan-treated OZR demonstrated significant (P < 0.05) dose-related decreases in systolic blood pressure, compared with blood pressures in untreated, control OZR. Despite the reductions in blood pressure, losartan had no significant effects on albuminuria or glomerular or tubulointerstitial injury. At 44 wk of age, the percentage (mean +/- SE) of glomeruli with sclerosis was 51 +/- 11, 49 +/- 9, and 39 +/- 14% in control OZR, low-dose (100 mg/L) losartan-treated OZR, and high-dose (200 mg/L) losartan-treated OZR, respectively (P > 0.05). Similarly, the tubulointerstitial injury score (range, 0 to 4) in the three groups was, respectively, 1.7 +/- 0.4, 1.6 +/- 0.3, and 1.5 +/- 0.3 (P > 0.05). It was concluded that in a setting of chronic renal failure where intrarenal RAS activity does not appear to be increased, angiotensin II receptor antagonism may not be nephroprotective despite a reduction in blood pressure.

Angiotensin Receptor Antagonists↗
PubMed1995

Isoprenoids and Ras: potential role in chronic rejection.

Protein prenylation, the post-translational attachment of isoprenoids to certain cellular proteins, increases protein hydrophobicity and promotes protein-membrane interactions. Of the many cellular proteins that undergo protein prenylation, particular attention has been paid to the protooncogene product Ras. Prenylated Ras protein localizes to the inner cell membrane and appears to function as a "molecular switch" through which peptide growth factors such as PDGF, IGF-1, and FGF, and cytokines such as IL-2, IL-6, and GM-CSF stimulate intracellular events. Binding of these substances to their respective receptors on target cells can activate Ras, triggering intracellular signaling cascades which culminate in processes such as cell proliferation, differentiation, and T-cell activation. Protein prenylation inhibitors block Ras prenylation, prevent membrane localization of Ras, and inhibit growth and proliferation of a variety of cell types. Recent studies in our laboratory have begun to examine the possible role of Ras in chronic allograft rejection. Abdominal aorta segments from donor Lewis rats were transplanted into Buffalo recipient rats. Recipients treated with the HMG-CoA reductase inhibitor lovastatin, which inhibits isoprenoid production, showed significantly decreased allograft intimal area after 12 weeks, when compared with untreated recipients. In a separate study, recipients treated with the agent leflunomide, which inhibits growth factor receptor tyrosine kinases that can activate Ras, had significantly decreased allograft intimal area after 12 weeks. These results suggest that Ras may be important in chronic allograft rejection, and that agents that interfere with Ras protein prenylation or activation by growth factor receptors may ameliorate chronic rejection.

Animals↗
PubMed1994

Low-dose combined therapy with fluvastatin and cholestyramine in hyperlipidemic patients.

OBJECTIVE: To compare the low-density lipoprotein (LDL) cholesterol-lowering efficacy of low-dose combinations of cholestyramine and fluvastatin. DESIGN: Randomized, double-blind, parallel group, placebo-controlled trial with a 24-week double-blind treatment period divided into three phases. SETTING: Office-based clinics. PATIENTS: Hypercholesterolemic, with LDL cholesterol of 4.14 mmol/L or greater (> or = 160 mg/dL) and plasma triglycerides of 3.39 mmol/L or less (< or = 300 mg/dL). Four hundred sixty patients were screened; 224 patients were randomized into a double-blind treatment period; 203 completed the study; 6 dropped out because of adverse events. INTERVENTION: Patients were treated with 10 mg or 20 mg of fluvastatin alone, 8 g or 16 g of cholestyramine alone, or combinations of these fluvastatin and cholestyramine dosages (six treatment groups). MEASUREMENTS: Changes in lipid variables, particularly LDL cholesterol. RESULTS: The 10-mg and 20-mg fluvastatin monotherapy groups showed considerable reductions in LDL cholesterol initially (-20.1% [SD, 8.8%] and -20.2% [SD, 10.1%], respectively); these reductions were maintained. Reductions in LDL cholesterol that resulted from the addition of cholestyramine, 8 g/d, to 10 mg of fluvastatin and 20 mg of fluvastatin were greater than those observed with monotherapy (10-mg fluvastatin--[10-mg fluvastatin plus cholestyramine], 9.1%; 95% CI, 3.8% to 14.4%) and 20-mg fluvastatin--[20-mg fluvastatin plus cholestyramine], 11.6%; CI, 6.5% to 16.8%). The increase in cholestyramine dose to 16 g/d in the three combination groups provided only a modest additional response. CONCLUSIONS: Low-density lipoprotein cholesterol reductions of about 25% to 30% can be achieved with low-dose combination therapy with fluvastatin and cholestyramine. The addition of low-dose resin appears to produce greater overall cholesterol reduction than does a simple doubling of the fluvastatin dosage. The low-dose combination treatment was highly successful in achieving the goals of the National Cholesterol Education Program guidelines.

Anticholesteremic Agents↗
PubMed1994

Pharmacokinetics of tazobactam M1 metabolite after administration of piperacillin/tazobactam in subjects with renal impairment.

Tazobactam is a new derivative of penicillinic acid sulfone, which functions as an irreversible inhibitor of many beta-lactamases. The disposition of tazobactam M1 metabolite after intravenous (i.v.) infusion of 3 g of piperacillin/0.375 g of tazobactam was evaluated in 26 subjects with various degrees of renal impairment. Participants in the study were 18 subjects with creatinine clearances (ClCR) ranging from 7.4-41.8 mL/min, 4 subjects maintained on continuous ambulatory peritoneal dialysis (CAPD), and 4 subjects undergoing chronic hemodialysis (HD). The pharmacokinetic parameters of piperacillin and tazobactam were evaluated and were similar to previous reports. Tazobactam M1 metabolite maximum plasma concentration increased as renal function declined. The terminal elimination half-life and area under the plasma concentration-time curve of the tazobactam M1 metabolite increased as renal function declined. The mean rate of recovery of the tazobactam M1 metabolite in hemodialysate during a 3- to 4.2-hour HD session 1 hour after the i.v. infusion of piperacillin/tazobactam was 25.3%. However, when HD was performed at 36-48 hours after the i.v. infusion, 57.6% of the tazobactam dose was recovered as M1 metabolite, suggesting further conversion of tazobactam to M1 metabolite. Peritoneal dialysis removed 15.8% (n = 2) of the tazobactam dose as the M1 metabolite. Using a dose of 3 g of piperacillin/0.375 g of tazobactam, the predicted maximum steady-state plasma concentrations of the tazobactam M1 metabolite are 14.6 micrograms/mL, 34.8 micrograms/mL, and 48.8 micrograms/mL for subjects with ClCR 20-40 mL/min (every 6 hour dosing), ClCR < 20 mL/min (every 8 hour dosing), and on CAPD (every 12 hour dosing), respectively.

Adult↗
PubMed1994

Influence of co-morbidity on mortality and morbidity in patients treated with hemodialysis.

It has been established that mortality among US end-stage renal disease patients is higher than in many other developed countries. The explanation for this apparent difference in outcome results has caused considerable concern. The explanations for this difference are complex and could include differences in case mix as well as indices of severity of illness. To evaluate potential patient-based explanations for these discrepancies, we have evaluated existing reports as well as the available database at the Regional Kidney Disease Program at Hennepin County Medical Center, with particular emphasis on medical co-morbidity present in US end-stage renal disease patients. These data indicate that increasing age, a greater prevalence of diabetes mellitus patients, and a greater proportion of end-stage renal disease patients with complex medical co-morbidity contribute to the higher mortality seen in US patients receiving hemodialytic therapies.

Comorbidity↗
PubMed1994

Effect of lipids on glomerular injury and progression of renal disease.

Experimental studies have suggested that the dyslipidemia that frequently accompanies models of progressive renal injury contributes to glomerular and interstitial injury. This concept is supported by experiments demonstrating that while dietary-induced hypercholesterolemia is associated with modest renal injury, in the presence of hypertension or proteinuria, there is a synergistic effect. In addition, strategies to reduce circulating lipids by the use of different classes of antilipemic agents have also significantly ameliorated glomerular injury. The mechanisms whereby lipids contribute to renal injury are still incompletely understood. However, a direct effect of lipids on the biology of mesangial cells has been demonstrated. In addition, evidence supporting a pathogenetic role for oxidatively-modified low density lipoprotein has been developed. Recent experimental studies have also suggested that antilipemic agents, particularly the 3-hydroxy-3-methylglutaryl coenzyme A inhibitor class, modify the proliferative response to various mitogenic substances. Together these data provide compelling support that lipids participate in the pathogenesis of progressive renal disease.

Animals↗
PubMed1994

Cholesterol synthesis inhibitors inhibit more than cholesterol synthesis.

The beneficial effects of HMG-CoA reductase inhibition in models of progressive glomerular injury may not all be due to reductions in circulating lipoproteins and decreases in glomerular lipoprotein deposition. Indeed, HMG-CoA reductase inhibitors may have direct effects on glomerular mesangial cells that could explain the amelioration of renal injury. Specifically, HMG-CoA reductase inhibitors block the synthesis of isoprenoids that are necessary for mesangial cell proliferation and other important cell functions. Thus, protein isoprenylation may play a critical role in the pathogenesis and treatment of lipid-induced glomerular injury.

Animals↗
PubMed1993

Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis.

OBJECTIVE: To assess the relative effect of different antihypertensive agents on proteinuria and renal function in patients with diabetes. DATA SOURCES: We used MEDLINE and bibliographies in recent articles to identify studies of the effects of antihypertensive agents on renal function in patients with diabetes. STUDY SELECTION: We selected 100 controlled and uncontrolled studies that provided data on renal function, proteinuria, or both, before and after treatment with an antihypertensive agent. DATA EXTRACTION: Data on blood pressure, renal function, proteinuria, patient characteristics (for example, age, sex, and type of diabetes), and study design (for example, random allocation and the use of a placebo) were extracted from selected studies. DATA SYNTHESIS: Multiple linear regression analysis indicated that angiotensin-converting enzyme (ACE) inhibitors decreased proteinuria independent of changes in blood pressure, treatment duration, and the type of diabetes or stage of nephropathy, as well as study design (P < 0.0001). Reductions in proteinuria from other antihypertensive agents could be entirely explained by changes in blood pressure. Blood pressure reduction in itself was associated with a relative increase in glomerular filtration rate (regression coefficient [+/- SE], 3.70 +/- .92 mL/min for each reduction of 10 mm Hg in mean arterial pressure; P = 0.0002); however, compared with other agents, ACE inhibitors had an additional favorable effect on glomerular filtration rate that was independent of blood pressure changes (3.41 +/- 1.71 mL/min; P = 0.05). CONCLUSION: Angiotensin-converting enzyme inhibitors can decrease proteinuria and preserve glomerular filtration rate in patients with diabetes. These effects occur independent of changes in systemic blood pressure.

Adolescent↗
PubMed1993

The disposition and protein binding of batanopride and its metabolites in subjects with renal impairment.

We have studied the disposition of batanopride and its three major metabolites (the erythro-alcohol, threo-alcohol, and N-desethyl metabolites) in 27 subjects with various degrees of renal function after intravenous infusion of a single dose of 3.6.mg.kg-1 of batanopride over 15 min. The subjects were assigned to one of three treatment groups: group 1, normal renal function (creatinine clearance > or = 75 ml.min-1 x 1.73 m-2; n = 13); group 2, moderate renal impairment (creatine clearance 30-60 ml.min-1 x 1.73 m-2; n = 8); group 3, severe renal impairment (creatinine clearance < or = 30 ml.min-1 x 1.73 m-2; n = 6). The terminal half-life of batanopride was significantly prolonged from 2.7 h in group 1 to 9.9 h in group 3. The renal clearance of batanopride was significantly lower in group 3 (25 ml.min-1) compared with group 1 (132 ml.min-1). There were no differences in plasma protein binding or steady-state volume of distribution of batanopride among the groups. There were significantly lower renal clearances for all three metabolites in groups 2 and 3 compared with group 1. The half-lives of all three metabolites were significantly prolonged in group 3 compared with group 1. The dose of batanopride may need to be reduced in patients with creatinine clearances less than 30 ml.min-1 x 1.73 m-2 to prevent drug accumulation and avoid possible dose-related adverse effects.

Adult↗
PubMed1993

Hypertension, hyperlipidemia, and renal damage.

Experimental studies have demonstrated that a number of factors participate in the progression of renal disease. Systemic and glomerular hypertension have been shown to be critical factors in renal injury. Hyperlipidemia that frequently coexists with renal disease also has been suggested as an important participatory factor in nephron damage. Interestingly, both hypertension and hyperlipidemia seem to evoke glomerular growth, a factor that has also been postulated to be involved in glomerular and tubular destruction. Recently, experimental and clinical data suggest that an important interaction occurs between hyperlipidemia and hypertension. Not only do they frequently coexist, but hypertension dramatically exaggerates hyperlipidemic injury, and hyperlipidemia alters systemic and glomerular vascular production of vasoactive substances which maintain basal vascular tone. Thus, these recent observations underscore the interactive potential of the various risk factors that participate in progression of renal disease. They also suggest that multiple interventional strategies may be needed to optimally prevent progressive nephron loss.

Animals↗
PubMed1993

Lovastatin retards the progression of established glomerular disease in obese Zucker rats.

Considerable experimental evidence indicates that hyperlipidemia can induce glomerular injury. The importance of lipids in the progression of established glomerular disease has not been established and is of clinical relevance because of the frequent association of lipid abnormalities with human renal disease. In the present study, 26-week-old hyperlipidemic obese Zucker rats (OZRs) with established nephropathy were treated for a period of 18 weeks with daily injections of the cholesterol synthesis inhibitor lovastatin (4 mg/kg). Compared with control OZRs treated with vehicle, lovastatin-treated OZRs had significantly (P < 0.05) lower serum cholesterol and triglyceride levels throughout the treatment period. Blood pressure and urine albumin excretion in lovastatin-treated OZRs were reduced over the first 12 weeks of therapy, but increased toward the levels in the control OZRs at the end of the protocol. After 18 weeks of therapy, the incidence of glomerulosclerosis in lovastatin-treated OZRs (23.2% +/- 5.8%) was approximately half of that in vehicle-treated OZRs (44.6% +/- 7.7%) (P < 0.05). The reduction in glomerular injury in lovastatin-treated OZRs was not associated with changes in either glomerular area or glomerular macrophage content. In separate experiments, mesangial cells were cultured from glomeruli isolated from 26-week-old proteinuric OZRs. Lovastatin (5 to 40 mumol/L) caused a significant dose-dependent inhibition of serum-stimulated mesangial cell DNA synthesis. The inhibitory effects of lovastatin were completely prevented in the presence of exogenous mevalonate (100 mumol/L). Thus, lovastatin retarded the progression of established glomerular disease in OZRs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Lipid abnormalities and changes in plasma proteins in glomerular diseases and chronic renal failure.

Lipid abnormalities are almost a constant feature of kidney disease. However, the contribution of deranged lipid metabolism to the increased incidence of cardiovascular disease among renal patients has not been definitely established. Conversely, the role of lipid abnormalities in the progression of renal disease has gained considerable experimental support. Both dietary and pharmacologic interventions, which reduce circulating lipid levels, have been proven to decrease the incidence of glomerulosclerosis in various animal models. Whether similar results can be achieved in renal patients is, at present, unknown. If the new lipid-lowering drugs prove useful in preventing the progression of both glomerulosclerosis and atherosclerosis, a major advance in the therapy for renal patients will be achieved.

Animals↗
PubMed1993

Treatment of hyperlipidemia in chronic progressive renal disease.

Experiments in animal models suggest that correcting abnormalities in lipid metabolism could help slow the rate of functional decline in patients with chronic progressive renal disease. Circumstantial evidence in humans also suggests that lipids may play a role in the pathogenesis of glomerulosclerosis. Nevertheless, large controlled clinical trials examining the effect of lipid-lowering strategies on renal disease progression have not been carried out. However, the recent development of antilipemic agents that appear to be safe and effective in patients with renal disease should make it possible to determine whether treating hyperlipidemia will reduce the rate of renal disease progression.

Animals↗
PubMed1993

Lovastatin inhibits proliferation of rat mesangial cells.

Products of intracellular mevalonate metabolism are essential for cell growth and proliferation. Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, blocks the formation of mevalonate and its metabolites, and has been shown to inhibit proliferation of several cell types. In vivo, lovastatin has reduced mesangial cellularity and glomerular injury in experimental renal disease. In this study, we investigated the effects of lovastatin on DNA replication and proliferation in rat glomerular mesangial cells. Growth-arrested mesangial cells were exposed to medium containing 10% fetal bovine serum to stimulate mitogenesis. Lovastatin (1-20 microM) caused a significant (P < 0.05) dose-dependent reduction in DNA synthesis ([3H]thymidine incorporation) which was completely prevented in the presence of exogenous mevalonate (100 microM). Lovastatin (1 microM) inhibited cell proliferation by 90% over a 5-d period, and this was largely overcome by added mevalonate. Exogenous low density lipoprotein (100 micrograms/ml) did not prevent lovastatin inhibition of DNA synthesis. The isoprenoid end product isopentenyl adenine (5 or 50 microM) had little effect on DNA synthesis and cell proliferation in lovastatin-blocked cells. By contrast, the isoprenoid farnesol (5 microM) largely prevented lovastatin inhibition of DNA synthesis. We conclude that mevalonate metabolism is essential for mesangial cell proliferation, possibly through the production of the isoprenoid farnesol. Moreover, the action of lovastatin to reduce experimental glomerular injury may involve a direct effect on mesangial cells.

Adenine↗