Biomedical subjects

W F Keane

Publications and source records attributed to W F Keane.

At least 91 records · Page 5Linked to original sources

PubMed1993

Alterations in glomerular proteoglycan metabolism in experimental non-insulin dependent diabetes mellitus.

Glomerular proteoglycans (PG) are important in modulating extracellular matrix assembly and glomerular permselectivity. In the obese Zucker rat, an experimental model of non-insulin dependent diabetes mellitus, expansion of the mesangial matrix, and microalbuminuria occur before the development of overt renal disease. The in vivo incorporation of (35S)sulfate into glomerular PG in 12-wk-old obese Zucker rats at the onset of microalbuminuria was compared with that of 12-wk-old lean Zucker rats. Specific (35S)sulfate incorporation into glomerular PG over 8 h was increased by 57% in obese rats compared with lean rats, suggesting increased PG synthesis. However, at variance with the observation in experimental models of insulin-dependent diabetes mellitus, the proportion of total glomerular (35S)PG released by heparin treatment was unchanged. Heparan sulfate (HS)-PG constituted over 60% of radiolabeled de novo synthesized glomerular PG. Similar proportions of HS-PG were extracted from the glomeruli of obese and lean rats. Isolated glomeruli spontaneously released two HS-PG, which constituted approximately 30% of total glomerular (35S)PG. On the basis of their chromatographic and electrophoretic patterns, these PG were similar in obese and lean rats. Heparin treatment of isolated glomeruli released an additional HS-PG, which appeared to be derived primarily from the glomerular extracellular matrix compartment and not from the detergent soluble cell fraction. Heparin-releasable HS-PG from both the lean and obese Zucker rats eluted at a KAV of 0.31 from Sepharose CL-6B chromatographic columns, indicating a hydrodynamic size similar to that reported for glomerular basement membrane HS-PG. However, gel electrophoresis demonstrated faster migration of the HS-PG released by heparin from the glomeruli of obese Zucker rats, suggesting increased electronegativity. Thus, early in the course of nephropathy in the obese Zucker rat, there is increased glomerular PG synthesis with no change in the proportions of the constitutively releasable and heparin-releasable HS-PG. Whether electrophoretic abnormalities of the heparin-releasable HS-PG observed in the obese rats contribute to the development of albuminuria and/or mesangial matrix expansion remains to be established.

Animals↗

PubMed1993

Oxidative modification of low-density lipoproteins by mesangial cells.

Because hypercholesterolemia and mesangial cell proliferation may be important in the pathogenesis of glomerulosclerosis, the effects of low-density lipoprotein (LDL) on human mesangial cell proliferation were evaluated. Native LDL (20 to 200 micrograms/mL) caused a dose-dependent increase in (3H)thymidine incorporation and increased mesangial cell numbers over 96 h. The mitogenic effect of LDL was partially blocked by the inhibition of cytochrome P-450, but not by the inhibition of cyclooxygenase or lipoxygenase pathways. Higher LDL concentrations (1,000 to 2,000 micrograms/mL) inhibited (3H)thymidine incorporation and reduced cell numbers, possibly as a result of the oxidative modification of LDL, indicated by an increase in thiobarbituric reactive substances. This peroxidation of LDL involved superoxide, because superoxide dismutase and butylated hydroxytoluene prevented it, whereas hydroxyl radical scavengers were without effect. Native LDL subjected to chemical oxidation by copper sulfate also inhibited mesangial cell proliferation. These results suggest that low concentrations of LDL may stimulate human mesangial cell proliferation, which may, in turn, cause the production of reactive oxygen molecules. Moreover, the oxidative modification of LDL may mediate the toxic effects of high LDL concentrations on human mesangial cells.

Antioxidants↗

PubMed1993

The renin-angiotensin system in the type II diabetic obese Zucker rat.

Recently, the obese Zucker rat (OZR), an animal model of non-insulin-dependent (type II) diabetes, was shown to respond to converting enzyme inhibition with decreased albuminuria and a marked attenuation of glomerular injury. It was hypothesized that the OZR would possess low plasma renin values and an increased vascular responsiveness to angiotensin II, and therefore, the renin-angiotensin system (PRA, active renin, inactive renin, renal renin content, and plasma angiotensinogen) and vascular reactivity in OZR at 10 and 24 wk of age were investigated. PRA and renin concentration, inactive plasma renin, and renal renin content were all significantly (P < 0.05) reduced in OZR when compared with age-matched lean controls. The ratio of inactive to total renin was significantly increased in the OZR. OZR aortic ring vascular reactivity to KCl, norepinephrine, and angiotensin II was assessed. Despite essentially equal or increased contractile responses to KCl and norepinephrine at both 10 and 24 wk of age, the OZR was not more sensitive to angiotensin II and displayed a significantly reduced contractile response to angiotensin II at 24 wk of age, when compared with lean age-matched controls. It was concluded that the renal protective effect of converting enzyme inhibition in OZR, despite significantly reduced PRA and concentration, inactive plasma renin, and renal renin content, may not be due to a diabetes-induced increased vascular reactivity to angiotensin II.

Angiotensin I↗

PubMed1993

The mevalonate pathway: importance in mesangial cell biology and glomerular disease.

Products of intracellular mevalonate metabolism are critical for the growth and proliferation of eukaryotic cells. These products include cholesterol and several nonsterol isoprenoids. The isoprenoid farnesyl is a particularly important intermediate in the mevalonate pathway. Farnesyl can be used to synthesize cholesterol and can also bind covalently to several low molecular mass GTP-binding proteins such as p21 ras. Farnesylated p21 ras may be critical for mitogenic signalling stimulated by growth factors such as platelet-derived growth factor. Inhibitors of the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, such as lovastatin and compactin, block the production of mevalonate and its metabolites. These agents have been shown to inhibit proliferation of many cell types. Recently we demonstrated that lovastatin inhibited proliferation of cultured glomerular mesangial cells. Lovastatin inhibition was overcome by the simultaneous addition of either mevalonate or farnesol, but not by exogenous low density lipoprotein cholesterol. These results suggested that farnesyl is critical for mesangial cell proliferation. In several experimental models of renal disease, chronic lovastatin administration reduced the extent of glomerular injury. The beneficial effects of lovastatin have been attributed to lowering of circulating lipid and lipoprotein levels. In view of recent data, however, it is possible that lovastatin may act to reduce glomerular injury, at least in part, through a direct action on mesangial cell proliferation.

Animals↗

PubMed1993

Peritoneal dialysis-related peritonitis treatment recommendations. 1993 update. The Ad Hoc Advisory Committee on Peritonitis Management. International Society for Peritoneal Dialysis.

In conclusion, the recommendations provided in this document represent a distillation of various experiences, as well as data obtained from published studies. It is hoped that this compilation will provide a basis upon which future developments and advances can be made in the therapeutic approach to infectious complications of peritoneal dialysis.

Anti-Bacterial Agents↗

PubMed1992

Applicability of teicoplanin dosage adjustment guidelines for renally impaired patients over the range of 3 to 30 mg kg-1.

The pharmacokinetics of teicoplanin were investigated in 13 subjects with various degrees of renal impairment using a randomized two-period crossover design; 11 subjects completed both periods. Doses of 3 and 30 mg kg-1 were administered as single dose, 60-min constant rate intravenous infusions. Blood samples were obtained over 28 days and urine was collected over 48 h. Serum and urine were analyzed using a microbiological assay. As previously observed in studies conducted in renally impaired subjects, teicoplanin total and renal clearance significantly decreased with decreasing creatinine clearance (p < 0.0001). However, for these parameters, no differences between doses were observed. Dosage adjustment guidelines for renally impaired patients are usually developed using the ratio of total clearance in renally impaired patients to the total clearance in patients with normal renal function. Since no dose-related differences existed in the relationship between teicoplanin total clearance and creatinine clearance, initial dosage adjustment guidelines for renally impaired patients developed at 3 or 30 mg kg-1 are applicable over the range of 3 to 30 mg kg-1.

Aged↗

PubMed1992

Effect of concomitant administration of piperacillin on the dispositions of isepamicin and gentamicin in patients with end-stage renal disease.

Piperacillin inactivation of the aminoglycosides isepamicin and gentamicin in 12 chronic hemodialysis patients was assessed. Six subjects each received isepamicin (7.5 mg/kg of body weight) or gentamicin (2 mg/kg) alone and in combination with piperacillin (4 g every 12 h for four doses). Isepamicin and gentamicin concentrations in plasma and urine were monitored over 48 h after each dose and analyzed by high-performance liquid chromatography and fluorescence polarization immunoassay, respectively. The pharmacokinetics of isepamicin were not significantly altered during combination treatment with piperacillin. The total body clearance (3.79 +/- 0.71 versus 3.94 +/- 1.05 ml/min), the steady-state volume of distribution (0.19 +/- 0.04 versus 0.18 +/- 0.03 liter/kg), and the terminal elimination half-life (47.91 +/- 7.20 versus 45.08 +/- 10.34 h) were not significantly altered in the presence of piperacillin. In contrast, the terminal elimination half-life (47.68 +/- 20.58 versus 35.67 +/- 11.18 h) of gentamicin was significantly reduced when gentamicin was given with piperacillin. The total body clearance (4.26 +/- 3.07 versus 4.89 +/- 1.94 ml/min) and the steady-state volume of distribution (0.19 +/- 0.04 versus 0.20 +/- 0.04 liter/kg) of gentamicin were not significantly altered during combination therapy; however, the nonrenal clearance of gentamicin administered in combination with piperacillin (3.56 +/- 0.38 ml/min) increased significantly compared with that of gentamicin (2.03 +/- 0.50 ml/min) given alone. The results of this study suggest that no additional dosage adjustment of isepamicin during concomitant therapy with piperacillin in hemodialysis patients is necessary. However, this does not preclude the need for appropriately ex vivo-handled specimens for monitoring isepamicin concentrations in plasma to ensure therapeutic efficacy and prevent toxicity. Furthermore, additional dosage adjustments may be necessary when gentamicin is used concomitantly with piperacillin, on the basis of the significant in vivo inactivation that takes place in end-stage renal disease patients.

Adult↗

PubMed1992

Renal injury in obese Zucker rats: glomerular hemodynamic alterations and effects of enalapril.

Angiotensin-converting enzyme inhibitors may ameliorate experimental glomerular injury by either hemodynamic or nonhemodynamic mechanisms. In a long-term study, we examined the effects of 30 wk of enalapril treatment on the development of glomerular disease in obese Zucker rats (OZR). Enalapril significantly (P less than 0.05) lowered blood pressure, fasting serum cholesterol, and urine albumin excretion in OZR throughout the experimental period. At 38 wk of age, enalapril-treated OZR had a sixfold reduction in the percent glomeruli exhibiting focal glomerulosclerosis and a 20-30% reduction in kidney weight and glomerular area. A separate micropuncture study in 22- to 26-wk-old rats revealed that untreated OZR with albuminuria and increased blood pressure had elevated glomerular capillary pressure (Pgc). Enalapril-treated OZR had less albuminuria and lower blood pressure, but Pgc was not reduced. The value of the transcapillary hydraulic pressure difference (delta P) in enalapril-treated OZR was intermediate between values in untreated OZR and lean Zucker rats. Thus enalapril markedly attenuated the development of glomerular injury in OZR. The salutary effects of enalapril may have involved a reduction in delta P coupled to a nonhemodynamic action, possibly restriction of glomerular growth or lowering of serum cholesterol.

Albuminuria↗

PubMed1992

The Zucker rat model of obesity, insulin resistance, hyperlipidemia, and renal injury.

Although the pathogenesis of obesity in OZR is unknown, the association among hyperinsulinemia, insulin resistance, and hyperlipidemia suggests that investigations using OZR may help define how a number of vascular disease risk factors interact to cause end-organ damage. Like other rat strains, OZR do not develop atherosclerosis spontaneously. Nevertheless, in an endothelial injury model, atherosclerosis was worse in OZR than in LZR. Perhaps more intriguing is the fact that OZR develop spontaneous glomerular injury. Although the mechanisms important in the development and progression of glomerular injury in OZR remain to be clarified, both lipid abnormalities and glomerular hemodynamic alterations could play a role.

Animals↗

PubMed1992

Lovastatin but not enalapril reduces glomerular injury in Dahl salt-sensitive rats.

Dahl salt-sensitive (S) rats fed a high salt diet develop hypertension, hyperlipidemia, and progressive renal disease. Previous studies have suggested that lipids may be important in the pathogenesis of glomerulosclerosis in Dahl S rats. To investigate this possibility, Dahl S rats fed 4% NaCl chow were treated chronically with the cholesterol synthesis inhibitor lovastatin. After 22 weeks, lovastatin-treated rats had a 38% reduction in serum cholesterol, a 76% reduction in urine albumin excretion, and one-sixth the incidence of focal glomerulosclerosis compared with vehicle-treated control rats. Blood pressure in lovastatin-treated rats was significantly (p < 0.05) lower than that in vehicle-treated rats both early in the study (4 weeks of treatment) and at the end of the protocol. Lovastatin had no effect on glomerular filtration rate or glomerular ultrafiltration dynamics. The efficacy of angiotensin converting enzyme inhibitors in attenuating proteinuria and experimental glomerular disease may be dependent on sodium intake. Thus, we also investigated the effects of long-term enalapril treatment on glomerular injury in Dahl S rats fed high salt chow. Enalapril treatment (50 or 200 mg/l drinking water) significantly lowered blood pressure in Dahl S rats, but did not significantly affect albuminuria or glomerulosclerosis. Enalapril also had no effect on glomerular hemodynamics. These results suggest that lipids may be important in the development of both glomerular disease and hypertension in Dahl S rats and that angiotensin converting enzyme inhibition may not affect the course of renal disease in a setting of high salt intake.

Albuminuria↗

PubMed1992

Is the aggressive management of hyperlipidemia in nephrotic syndrome mandatory?

The development of the nephrotic syndrome is associated with a lipid profile characterized by increased total and low density lipoprotein cholesterol. Although total high density lipoprotein (HDL) values may be in the normal range, there is frequently abnormalities of HDL subclasses, with reduction of the mature HDL2 subfraction. While these lipid changes may be considered a risk for atherosclerosis, they revert to normal with remission of the nephrotic syndrome. However, with chronic nephrotic range proteinuria, these abnormalities persist and may also be associated with increased levels of lipoprotein (a), increased levels of very light density lipoprotein and further reductions in HDL. These factors could all contribute to greater risk for atherosclerosis. Although coronary artery disease is frequently seen in patients with end-stage renal disease, and many uncontrolled studies in patients with chronic nephrotic syndrome have suggested an increased prevalence of cardiovascular disease, no prospective studies to evaluate relationship between lipid abnormalities and cardiac disease have been performed in patients with the nephrotic syndrome. Recent experimental data have also suggested a relationship between hyperlipidemia and progressive renal injury. Unfortunately, human epidemiological data are incomplete in correlating lipid changes with renal disease in patients with chronic nephrotic syndrome. No therapeutic trials have tested whether or not pharmacologic interventions will benefit either the cardiac or renal disease that ensues in patients with chronic persistent nephrotic syndrome. Thus, considerably more data are needed to help clarify this important area.

Cardiovascular Diseases↗

PubMed1992

Cholesterol-lowering effects of calcium carbonate in patients with mild to moderate hypercholesterolemia.

BACKGROUND: In recent years, several authors have noted that oral calcium treatment was associated with a reduction in serum cholesterol level. METHODS: Calcium carbonate was examined for its ability to lower serum cholesterol levels in hypercholesterolemic patients. Fifty-six patients with mild to moderate hypercholesterolemia were examined in this randomized, double-blind, placebo-controlled crossover study. Patients were treated with a low-fat, low-cholesterol diet targeted at the American Heart Association Step-1 diet for 8 weeks before and while receiving placebo or calcium carbonate (9.98 mmol [400 mg] of elemental calcium) three times daily with meals for 6 weeks. Patients were then crossed over to the alternate treatment for an additional 6-week period. RESULTS: Compared with placebo, calcium carbonate achieved a 4.4% reduction in the low-density lipoprotein cholesterol level, and a 4.1% increase in the high-density lipoprotein cholesterol level. The ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol significantly decreased by 6.5% with calcium carbonate treatment. Calcium carbonate treatment did not significantly affect blood pressure or serum levels of triglycerides, lipoprotein Apo B, or calcium. Relative urinary saturation ratios of calcium oxalate levels were unchanged during calcium carbonate therapy. Compliance with diet and treatment was excellent and no significant adverse effects were noted. CONCLUSIONS: Thus, calcium carbonate was a modestly effective and well-tolerated adjunct to diet in the management of mild to moderate hypercholesterolemia in this clinical study.

Adult↗

PubMed1991

Impact of dietary fatty acid supplementation on renal injury in obese Zucker rats.

We previously reported that renal injury in hyperlipidemic, obese Zucker rats was associated with a relative deficiency of tissue polyunsaturated fatty acids (PUFA). In the present study 10-week-old obese Zucker rats were pair fed regular chow or chow containing either 20% sunflower oil rich in n-6 PUFA, fish oil rich in n-3 PUFA, coconut oil medium-chain saturated fatty acid, or beef tallow long-chain saturated fatty acid. At 34 weeks of age there were comparable reductions in albuminuria, mesangial matrix expansion, and glomerulosclerosis in the fish oil and sunflower oil groups. While both fish oil and sunflower oil reduced serum triglycerides, and improved the composition of triglyceride-enriched lipoproteins, only fish oil decreased serum cholesterol. The effect of the dietary fatty acid supplementation on fatty acid profiles were similar in isolated glomeruli and cortical tissue. In general, the amelioration in injury in the fish oil and sunflower oil fed rats was most closely linked to glomerular levels of PUFA, either n-6 or n-3. These data suggest that hyperlipidemia and abnormalities in tissue FA are closely linked, and that dietary supplementation with PUFA may ameliorate chronic, progressive renal injury.

Albuminuria↗

PubMed1991

Pharmacokinetics of ceftibuten-cis and its trans metabolite in healthy volunteers and in patients with chronic renal insufficiency.

The impact of renal insufficiency on the dispositions of 300 mg of orally administered ceftibuten-cis, a new broad-spectrum oral cephalosporin, and its primary metabolite ceftibuten-trans was characterized in 30 adult subjects. Subjects were divided into five groups of six subjects each on the basis of their 24-h ambulatory creatinine clearances (CLCR). The apparent total body clearance (CLP/F; where F is absolute bioavailability) and renal clearance of ceftibuten-cis were significantly lower in subjects with end-stage renal disease (on maintenance hemodialysis; group V) and in those with severe (CLCR, 5 to 29 ml/min; group IV) and moderate (CLCR, 30 to 49 ml/min; group III) renal insufficiency than in those with mild renal insufficiency (CLCR, 50 to 80 ml/min; group II) or normal renal function (CLCR, greater than 80 ml/min; group I). A significant correlation was observed between CLCR and ceftibuten-cis CLP/F. The mean apparent steady-state volume of distribution (V beta/F) of ceftibuten-cis ranged from 0.21 to 0.24 liter/kg in subjects in group I, II, III, and IV. V beta/F was significantly greater in the group V subjects with end-stage renal disease (V beta/F, 0.39 +/- 0.27 liters/kg). These changes in V beta/F cannot be separated from possible changes in bioavailability. The maximum concentration of ceftibuten-trans in plasma was significantly higher and occurred significantly later in group IV subjects than it did in subjects in the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1991

Adjunctive therapy with intravenous human immunoglobulin G improves survival of patients with acute renal failure.

The objective of this prospective, randomized, double-blind, placebo-controlled clinical trial was to evaluate the efficacy of adjunctive therapy with iv human immunoglobulin G in reducing the morbidity and mortality associated with acute renal failure. Forty patients greater than or equal to 18 yr of age who were identified within 48 h of the onset of acute renal failure and who met the enrollment criteria were enrolled in the study. Thirty-five patients were considered evaluable. Patients were grouped according to the admitting service (medical or surgical/trauma) and were randomized to receive either immunoglobulin G (400 mg/kg body wt) or placebo (normal saline; 8 mL/kg body wt) at study entry and then weekly thereafter for a maximum of 4 doses. The groups were well balanced with respect to demographics, clinical presentation, and severity of illness (APACHE II scores). A significant reduction in mortality at 42 days after study entry was observed. Two of 17 (12%) patients in the immunoglobulin G-treated group compared with 8 of 18 (44%) patients in the placebo-treated group died (P = 0.025). No differences were observed in the frequency of major complications that occurred in association with acute renal failure. However, in patients who manifested infection, greater survival was observed in the immunoglobulin G treatment group. The results suggest that immunoglobulin G administered at the onset of acute renal failure reduced mortality possibly by decreasing the severity of infectious complications associated with the occurrence of of acute renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗

PubMed1991

Antimicrobial treatment of peritonitis associated with continuous ambulatory peritoneal dialysis.

A multitude of therapeutic regimens have been proposed for the management of peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD). There are, however, few clinical trials that have evaluated the efficacy of these proposed regimens in a prospective, comparative fashion. This retrospective report is a tabulation of the published data on antimicrobial treatment of CAPD-related peritonitis. The results are presented for combination and mono-drug therapies; Gram-positive bacterial, Gram-negative bacterial and fungal infections; intravenous, oral and intraperitoneal (i.p.) routes of drug administration; various dosages and dosing intervals; and clinical response and relapse rates. The apparent optimal combination regimen for empiric treatment of peritonitis is vancomycin administered in 1 dialysis exchange/week with ceftazidime. This regimen avoids the toxicity associated with the use of aminoglycosides while maintaining effectiveness.

Anti-Bacterial Agents↗

PubMed1991

Glomerular hemodynamic effects of dietary polyunsaturated fatty acid supplementation.

Dietary supplementation with polyunsaturated fatty acids (PUFAs) has been shown to alter the course of experimental renal disease. Although hemodynamic factors such as glomerular hypertension are felt to be important in the progression of renal disease, the effects of dietary PUFA supplementation on glomerular hemodynamics are unknown. The present investigation, therefore, was designed to evaluate the glomerular hemodynamic effects of dietary PUFA supplementation in normal rats. Male Sprague-Dawley rats were fed standard chow supplemented with either 20% (wt/wt) fish oil (FO) as a source of omega-3 PUFAs, 20% sunflower oil (SO) as a source of omega-6 PUFAs, or 20% coconut oil (CO) as a control diet. Micropuncture studies were performed after 4 to 6 weeks of dietary supplementation. Compared with CO rats, SO rats did not demonstrate any changes in glomerular hemodynamics. However, rats supplemented with FO demonstrated significant (p less than 0.05) increases in both single nephron glomerular filtration rate and single nephron plasma flow. These hemodynamic changes were not associated with alterations in glomerular capillary hydraulic pressure or the glomerular ultrafiltration coefficient. The increase in SNPF was primarily the consequence of a 37% reduction (p less than 0.05) in efferent arteriolar resistance. Thus dietary FO supplementation resulted in glomerular hyperfiltration and hyperperfusion. These hemodynamic actions may have important consequences in determining the effect of omega-3 PUFAs on the course of experimental and clinical renal disease.

Animals↗

PubMed1991

Role of lipid peroxidation in the inhibition of mononuclear cell proliferation by normal lipoproteins.

Stimulated peripheral blood mononuclear cells (PBMC) can oxidize normal lipoproteins, and sufficiently oxidized lipoproteins are cytotoxic. However, the role of lipid peroxidation in the inhibition of mitogen-stimulated PBMC proliferation by physiologic concentrations of normal lipoproteins is unclear. In the present investigation, normal low density lipoprotein (LDL) and very low density lipoprotein (VLDL) suppressed [3H]thymidine incorporation and gamma interferon production in concanavalin A-stimulated PBMC without causing cell death. This suppression was accompanied by parallel increases in lipid peroxidation products measured as thiobarbituric acid reactive substances (TBARS). In contrast, high density lipoprotein (HDL) failed to inhibit PBMC and TBARS remains low. Differences between the PBMC suppression from LDL, VLDL, and HDL were best accounted for by normalizing the lipoprotein concentrations by their total lipid content. Moreover, the antioxidants superoxide dismutase and butylated hydroxytoluene each substantially ameliorated the inhibition of PBMC caused by LDL, and reduced the levels of lipid peroxidation products that were generated. Altogether, these results suggest that reactive oxygen species generated by stimulated PMBC may cause oxidative alterations of normal lipoproteins that may, in turn, account for much of the previously reported inhibition of PBMC by normal lipoproteins.

Antioxidants↗