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Biomedical subjects

W F Keane

Publications and source records attributed to W F Keane.

At least 55 records · Page 3Linked to original sources
PubMed1997

Irbesartan lowers blood pressure and ameliorates renal injury in experimental non-insulin-dependent diabetes mellitus.

In the present study, we investigated the effects of the angiotensin (Ang) II receptor antagonist, irbesartan, on blood pressure and renal structural injury in obese Zucker rats (OZR), an experimental model of non-insulin-dependent diabetes mellitus (NIDDM). Twenty-six-week-old OZR with established renal disease were administered either low-dose (15 mg/kg) or high-dose (50 mg/kg) irbesartan in the drinking water for a period of 18 weeks. Irbesartan caused dose-related reductions in blood pressure, and reduced by 47 to 60% the percent of glomeruli with sclerosis at 44 weeks of age (P < 0.05). In addition, irbesartan at the higher dose reduced the tubulointerstitial injury score at 44 weeks by approximately 75% (P < 0.05). By contrast, irbesartan did not significantly reduce albuminuria in OZR. The results of the present study demonstrate that the Ang II receptor antagonist irbesartan can reduce blood pressure and ameliorate glomerular and tubulointerstitial injury in an experimental model of NIDDM.

Albuminuria↗
PubMed1996

Lovastatin inhibits lipopolysaccharide-induced NF-kappaB activation in human mesangial cells.

BACKGROUND: HMG-CoA reductase inhibitors have been shown to reduce glomerular injury in different models of progressive renal damage. The transcription factor NF-kappaB plays a major role in the induced expression of genes involved in cellular proliferation and inflammatory responses that could be important in the pathogenesis of glomerular injury. We therefore examined the effects of the HMG-CoA reductase inhibitor lovastatin on NFkappaB activation in human mesangial cells. METHODS: Cultured human mesangial cells were stimulated with bacterial lipopolysaccharide (LPS) in the presence or absence of lovastatin. NF-kappaB activity was measured by electrophoretic mobility shift assay (EMSA). RESULTS: LPS-stimulated mesangial cells exhibited an NF-kappaB-like activity as assessed by EMSA competition assays, and supershift assays with antibodies against the p50 and p65 subunits of NF-kappaB. Treatment of mesangial cells with lovstatin in the presence of exogenous cholesterol resulted in a significant reduction of the LPS-induced NF-kappaB activity. In the presence of either mevalonate or the mevalonate metabolite farnesyl pyrophosphate, the lovastatin inhibition of NF-kappaB activation was substantially reversed, supporting a role for mevalonate metabolites in LPS-induced mesangial cell NF-kappaB activation. CONCLUSIONS: These data suggest an additional mechanism by which HMG-CoA reductase inhibitors may reduce glomerular injury, namely, by inhibiting NF-kappaB activation and the subsequent proliferative and inflammatory responses.

Base Sequence↗
PubMed1996

Effects of lipids on the pathogenesis of progressive renal failure: role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in the prevention of glomerulosclerosis.

Increasing experimental evidence suggests that lipids might be important modulators in progressive glomerulosclerosis. The inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase have demonstrated beneficial effects in different models of progressive renal failure. Monocyte infiltration, mesangial cell proliferation and mesangial matrix expansion have been shown to be early events in the process of glomerulosclerosis that can be lessened by HMG-CoA reductase inhibition. Recent experimental data suggest that these agents may also have glomerular protective effects independent of a reduction in circulating lipids. In vitro, lovastatin has been shown to downregulate mesangial cell production of monocyte chemoattractant protein-1 and colony-stimulating factor. In addition, HMG-CoA reductase inhibitors can directly reduce mesangial cell proliferation. These effects appear related to the ability of this class of agents to inhibit mesangial cell formation of intermediates of cholesterol formation, the nonsterol isoprenoids. Although low density lipoprotein cholesterol can induce mesangial cells to increase synthesis of matrix proteins, e.g., type-IV collagen, we have shown that lovastatin does not directly influence mesangial cell type-IV collagen metabolism. Thus, prevention of mesangial matrix expansion in vivo with type-IV collagen by HMG-CoA reductase inhibitors could be related to an indirect mechanism related to inhibition of monocyte influx into the glomerulus. Alternatively, a direct effect of these agents, through their cholesterol-lowering capabilities, could play a role in reducing matrix expansion.

Animals↗
PubMed1996

Pathogenesis of atherosclerosis.

Atherosclerosis, a common and complex disease, results from multiple interactions among injurious stimuli and the healing or reparative responses of the arterial wall. After endothelial injury, direct cell-cell interaction, and secretion of chemotactic and growth factors resulting from endothelial cell dysfunction, induce recruitment of monocytes to subintimal regions, smooth muscle cell proliferation, and increased synthesis of matrix proteins. The recruited monocytes become macrophages, accumulate lipid, and ultimately become foam cells. Together with accompanying T lymphocytes, these changes represent the fatty streak, an early histopathological change indicating atherosclerosis. Progression of this atherosclerotic lesion is marked by the accumulation of alternating layers of smooth muscle cells and lipid-laden macrophages. The advanced lesions of atherosclerosis compromise the lumen diameter and, thus, reduce the blood flow in arteries and ultimately participate in the mechanisms that lead to occlusion of the involved arteries.

Animals↗
PubMed1996

Lipids and progressive renal failure.

Experimental evidence suggests that lipids may modulate progressive renal injury. The inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase have demonstrated beneficial effects in different models of progressive renal failure. Recent experimental data suggests that these agents also may have glomerular protective effects independent of reduction in circulating lipids. Monocyte infiltration, mesangial cell proliferation and mesangial matrix expansion have been shown to be early events in the process of glomerulosclerosis that can be lessened by HMG-CoA reductase inhibition. In vitro, HMG-CoA reductase inhibitors have been shown to inhibit mesangial cell proliferation, as well as the production of chemokines involved in macrophage biology. These effects appear to be related to a reduction in cell production of cholesterol precursors, the so-called nonsterol isoprenoids. The isoprenoids are an important class of lipids necessary for isoprenylation of proteins such Ras, which are involved in cell signaling for various growth-promoting cytokines. We have also shown that interference with this signaling pathway results in marked reduction in the activation of nuclear transcription factors. Thus, it would appear that the HMG-CoA reductase inhibitors have the potential of modifying mesangial cell biology independent of any lipid-lowering effect. Clinically, a number of studies have shown that increased lipids are associated with an accelerated rate of progression of renal disease. Indeed, these lipid abnormalities are evident in the diabetic patient at the onset of microalbuminuria. In diabetic and nondiabetic patients, preliminary studies have suggested that interventions with these agents may have salutary effects on the progression of renal disease. Recently, experimental and clinical studies have also suggested that HMG-CoA reductase inhibitors may also reduce the severity of chronic vascular rejection.

Animals↗
PubMed1996

Risk factors for nephropathy and cardiovascular disease in diabetic Northern Minnesota American Indians.

Although complications of diabetes are common among Southwest American Indians, little is known about diabetes and associated risk factors for nephropathy and cardiovascular disease in other genetically distinct tribes. We conducted a retrospective analysis of 665 diabetic patients at two Chippewa Indian reservations in northern Minnesota to evaluate the prevalence of risk factors for diabetic nephropathy and cardiovascular disease. In 79 patients, a more detailed study was carried out, including an assessment of renal function and urinary albumin excretion (UAE). The overall prevalences of proteinuria and hypertension were 47.9% and 62.6%, respectively. Proteinuria was observed more often in hypertensive than in non-hypertensive patients (55.2% vs 44.4%, p < 0.05), and in patients with diabetes for longer than 10 years (57% vs 40% for diabetes less than 10 years, p < 0.05). Although hypercholesterolemia (total cholesterol > or = 200 mg/dl) was observed in 54% of patients, there was no relationship between hypercholesterolemia and proteinuria. In the 79 patients studied in more detail, UAE was greater in hypertensive patients compared to non-hypertensive patients (606 +/- 15600 mg/24h vs 101 +/- 157 mg/24 h, p < 0.05), and in patients with diabetes for 10 years or longer compared to patients in the first decade of disease (748 +/- 1732 mg/24 h vs 96 +/- 171 mg/24 h, p < 0.05). Hypercholesterolemia and elevated LDL-cholesterol (> 130 mg/dl) were observed in 56% and 49% of patients, respectively, but were not associated with increased UAE. In contrast, hypertriglyceridemia (> 250 mg/dl) was associated with an elevated UAE (932 +/- 2150 mg/24 h vs 245 +/- 735 mg/24h, p < 0.05). Increased lipoprotein(a) was found in patients with overt albuminuria. In summary, the prevalence of risk factors for diabetic nephropathy and associated cardiovascular disease is high in Chippewa American Indians in northern Minnesota. Although detecting abnormal UAE may be useful in identifying high-risk patients who may benefit from early intervention, traditional risk factors such as hypercholesterolemia may not explain the risk associated with increased UAE.

Adolescent↗
PubMed1995

Disposition of misoprostol and its active metabolite in patients with normal and impaired renal function.

The disposition of misoprostol acid, the active metabolite of misoprostol, was studied in 48 subjects with various degrees of renal function after administration of a single 400 microgram oral dose of misoprostol. Subjects were assigned to one of four treatment groups: group 1, normal renal function with creatinine clearance (CLCR) 80-140 mL/min/1.73 m2; group 2, mild renal impairment with CLCR 50-79 mL/min/1.73 m2; group 3, moderate renal impairment with CLCR 20-49 mL/min/1.73 m2 or group 4, end stage renal disease (ESRD) patients maintained on hemodialysis. The maximum plasma concentration (Cmax) and time to reach Cmax (tmax) for misoprostol acid tended to be larger in group 4 subjects; however, it failed to reach statistical significance. Although not statistically significant, in group 4 subjects the terminal half-life (t1/2) of misoprostol acid was almost twice as large (1.27 +/- 0.77 h) as in groups 1, 2, and 3 (0.70 +/- 0.72, 0.72 +/- 0.67, and 0.73 +/- 0.45 h, respectively). Misoprostol acid's total area under the plasma concentration curve (AUC0 infinity) was larger in group 4 subjects (1173.5 +/- 487.4 pg.h/mL) as compared with groups 1, 2, and 3 (421.4 +/- 263.1, 418.9 +/- 114.5, and 377.0 +/- 145.2 pg.h/mL, respectively; P < .05). The apparent total body clearance (CL) of misoprostol acid was statistically significantly smaller in group 4 subjects (0.094 +/- 0.044 L/kg/min) as compared only with group 3 subjects (0.284 +/- 0.102 L/kg/min). The dose of misoprostol may need to be reduced in ESRD patients on prolonged hemodialysis to prevent unnecessary high plasma levels of misoprostol acid and to avoid possible dose-related adverse effects.

Acute Kidney Injury↗
PubMed1995

Disposition of gabapentin in anuric subjects on hemodialysis.

Gabapentin is an anticonvulsant drug, which in man is cleared solely by renal excretion and is not bound to plasma proteins. Because the clearance of gabapentin is dependent on renal function, the pharmacokinetics of gabapentin were investigated in anuric subjects maintained on hemodialysis. Plasma samples were obtained over an 8-day period after administration of single oral 400-mg doses of gabapentin. Pre- and post-dialyzer plasma samples and dialysate samples from quantitative collection of dialyzer effluent were obtained during hemodialysis sessions performed 2, 4, and 7 days after dosing. A mean (SD) maximum gabapentin plasma concentration of 6.0 (2.4) micrograms/mL was achieved at 4.7 (2.1) hours post-dose. The elimination half-life of gabapentin on non-hemodialysis days averaged 132 hours. Approximately 35% of the gabapentin dose was recovered in dialysate, and mean hemodialysis clearance of gabapentin was 142 (26) mL/min; approximately 93% of the dialyzer creatinine clearance. Gabapentin elimination half-life during hemodialysis was approximately 4 hours. Systemic plasma gabapentin concentrations increased approximately 30% during the first 2 hours after hemodialysis as a result of drug redistribution in the body. It is recommended that patients with end-stage renal disease maintained on hemodialysis receive an initial 300-mg to 400-mg gabapentin loading dose. Plasma gabapentin concentrations can be maintained by giving 200 to 300 mg of gabapentin after every 4 hours of hemodialysis.

Acetates↗
PubMed1995

The pharmacokinetics of aminoguanidine in end-stage renal disease patients on hemodialysis.

Aminoguanidine is an investigational agent that may slow or prevent many diabetes-related complications. Since the elimination of aminoguanidine is dependent on renal function, its pharmacokinetics was investigated in eight chronic renal failure patients maintained on hemodialysis. Each patient received 300 mg of aminoguanidine hydrochloride during both an interdialytic and an intradialytic period. During the interdialytic period, the maximum aminoguanidine concentration (Cmax) and time to reach Cmax was 4.5 micrograms/mL and 1.5 hours, respectively. The terminal elimination half-life in these patients was prolonged (37.9 hours). The renal clearance was 2.1 mL/min. Only 8.7% of the administered dose was recovered unchanged in the urine, which is markedly reduced from what is recovered in urine in subjects with normal renal function. There was a positive correlation between the renal clearance of aminoguanidine and the patients' residual renal function (P < 0.05). During hemodialysis, the half-life of aminoguanidine was shortened to 3.9 hours. The hemodialysis clearance of aminoguanidine was 203.6 mL/min. After cessation of hemodialysis, a significant rebound in plasma aminoguanidine concentrations (mean, 39%) was observed. Thus, the dose of aminoguanidine hydrochloride will need to be significantly reduced in patients with end-stage renal disease. Given the interdialytic and intradialytic pharmacokinetics of aminoguanidine, three times weekly dosing after each hemodialysis session is suggested.

Diabetic Nephropathies↗
PubMed1995

Early glomerular changes in rats with dietary-induced hypercholesterolemia.

Increasing evidence suggests that lipids may be important modulators of progressive glomerular injury. We previously reported the long-term glomerular changes in rats with dietary-induced hypercholesterolemia. In this work, we evaluated the early glomerular changes induced by hypercholesterolemia that precede the development of glomerulosclerosis. In cholesterol-fed rats, an early macrophage influx was observed. This was associated with an increase in glomerular size, mesangial matrix expansion, lipid deposits, and foam cell formation. Immunohistochemical techniques showed that type IV collagen, fibronectin, and laminin were increased in cholesterol-fed rats. The mRNA expression for the alpha 1 chain of type IV collagen and an inhibitor of type IV collagenase were increased, suggesting that both increased synthesis and reduced degradation may be involved in cholesterol-induced mesangial matrix accumulation. The glomerular mRNA expression of transforming growth factor-beta 1 was also upregulated, suggesting that transforming growth factor-beta 1 could be an important mediator for mesangial matrix accumulation in hypercholesterolemic states. The early cholesterol-induced changes in the glomerulus are reminiscent in many respects to the process leading to glomerulosclerosis in the vessel wall.

Animals↗
PubMed1995

Screening and management of microalbuminuria in patients with diabetes mellitus: recommendations to the Scientific Advisory Board of the National Kidney Foundation from an ad hoc committee of the Council on Diabetes Mellitus of the National Kidney Foundation.

All individuals with diabetes mellitus should be screened yearly with a spot urine albumin:creatinine ratio to identify those who are at increased risk for the development of complications of diabetes mellitus, including nephropathy, retinopathy, and cardiovascular disease. Once these high-risk individuals are appropriately identified, it is recommended that therapy with an angiotensin-converting enzyme (ACE) inhibitor be initiated. In addition, cardiovascular risk factors should be investigated, and when appropriate, therapeutic interventions should be initiated according to existing recommendations.

Albuminuria↗