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D C Wheeler

Publications and source records attributed to D C Wheeler.

At least 37 records · Page 2Linked to original sources
PubMed1998

Low-density lipoprotein subfraction profiles in chronic renal failure.

BACKGROUND: Small low-density lipoprotein (LDL) particle size, a newly recognized risk factor for cardiovascular disease in the general population, is frequently associated with hypertriglyceridaemia, the predominant plasma lipid abnormality present in uraemia. METHODS: Plasma lipids and LDL subfraction profiles were examined in 33 non-dialysed patients with chronic renal failure (predial), 40 patients on continuous ambulatory peritoneal dialysis (CAPD), 42 haemodialysis patients (HD), 47 renal transplant recipients (RTR), and 44 controls. LDL subfractions separated by gel electrophoresis were scored by densitometric analysis (higher scores indicate profiles comprising smaller particles). RESULTS: All groups with renal failure had significantly elevated (mean+/-SD) LDL scores (predial 1.36+/-0.6, CAPD 1.71+/-0.9, HD 1.68+/-0.9, RTR 1.92+0.8 vs control 0.87+0.4, all P<0.001), this being the only lipid abnormality detected in the predialysis patients. In CAPD and HD patients, LDL scores were associated with serum triglyceride (r=0.81, P<0.001 and r=0.70, P<0.001 respectively), cholesterol (r=0.55, P<0.001 and r=0.49, P<0.01) and HDL-cholesterol (r= -0.43, P<0.01 and r= -0.51, P<0.01), whilst no such relationship was seen in the predialysis and RTR groups, suggesting that other factors were important. CONCLUSIONS: The presence of small LDL particles appears to be an early and unexplained feature of the uraemic dyslipidaemia. This abnormality persists after renal transplantation and may represent an important atherogenic risk factor.

Adrenergic beta-Antagonists↗
PubMed1998

Statins and the kidney.

Experience to date suggests that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins can be used relatively safely and effectively to treat dyslipidaemia complicating renal disease. Recent studies suggest that in addition to lowering plasma lipid levels, these drugs modify other factors that contribute to vascular injury. Furthermore, statins could slow the progression of chronic renal failure and may augment the action of immunosuppressive therapy after renal transplantation. Such newly defined actions, some of which could be unrelated to lipid lowering, are likely to extend the applications of statins in nephrology.

Animals↗
PubMed1998

Are there potential non-lipid-lowering uses of statins?

Recent clinical trials have demonstrated beyond doubt that statins are effective in the prevention of acute coronary events. Critical analysis of these studies suggests that the benefits of statin therapy cannot be fully explained on the basis of reductions in plasma cholesterol levels. Accumulating knowledge of the actions of these drugs shows that they may prevent several processes that eventually lead to plaque rupture and the development of occlusive thrombosis, the basis of acute coronary events. Hence, statins may correct endothelial dysfunction (thus protecting against ischaemic injury), stabilise existing plaques and modify the coagulation pathway, thereby reducing the likelihood of a sudden vascular event. At a cellular level, these drugs inhibit the synthesis not just of cholesterol, but of other compounds important in cell proliferation. Antiproliferative effects have been demonstrated in vitro and may broaden the applications of statins to the treatment of noncardiovascular diseases. Finally, preliminary clinical studies indicate that as a result of immunosuppressive actions, statins may reduce the incidence of rejection following organ transplantation.

Animals↗
PubMed1997

Association of vasculitic glomerulonephritis with membranous nephropathy: a report of 10 cases.

BACKGROUND: The concomitant occurrence of a vasculitic glomerulonephritis and membranous nephropathy in the same patient is unusual. We report data on 10 patients with this unusual combination. METHODS: Ten patients (nine males/one female; median age 63.5 years, range 30-70 years) presented between 1981 and 1995 with: acute renal failure (n = 3), nephrotic syndrome (n = 4), non-nephrotic range proteinuria and renal insufficiency (n = 3). The median serum creatinine at presentation was 296 mumol/l (range 65-1749 mumol/l). One patient had a vasculitic transformation from membranous nephropathy 5 years after the original presentation, coincident with an acute deterioration of renal function requiring dialysis; in all other patients the two glomerular disorders were seen together at presentation. Treatment was with oral prednisolone and cyclophosphamide (eight patients), of whom one also had plasma exchange; and oral prednisolone and azathioprine (one patient). Specific immunosuppressive treatment was withheld in one patient with histological evidence of chronic renal damage. Sera from four patients out of nine tested were positive for ANCA. RESULTS: After a median follow-up of 3.5 years (range 2 months-10 years), renal function had improved in three patients and remained stable in two. Two patients required renal replacement therapy. Three patients had died: one was ANCA-negative and died of a systemic vasculitis, and the other two died of sepsis. CONCLUSION: Membranous nephropathy complicated by a vasculitic glomerulonephritis: (1) has a more aggressive clinical course than membranous nephropathy alone, (2) appears to have an association with ANCA, (3) should be considered in those patients with an accelerated decline in renal function, and (4) may respond to treatment with immunosuppressive drugs.

Adult↗
PubMed1997

Focal segmental necrotizing glomerulonephritis in rheumatoid arthritis.

We report ten patients with rheumatoid arthritis (RA) who developed a focal segmental necrotizing glomerulonephritis (FSNGN) and extracapillary proliferation typical of vasculitic glomerulonephritis. Five patients also had extrarenal vasculitis. Renal presentation was with renal impairment (n = 9) (median creatinine 726 mumol/l, range 230-1592 mumol/l), microscopic haematuria (n = 8) and proteinuria (n = 10). Nine patients were seropositive for rheumatoid factor and nine had bone erosions. Serum from four of five patients tested by indirect immunofluorescence was positive for antineutrophil cytoplasmic antibody (ANCA) with perinuclear staining. Only three patients had penicillamine or gold therapy. Treatment was with prednisolone and cyclophosphamide (six patients, two of whom were also plasma-exchanged), prednisolone and azathioprine (two patients) and prednisolone alone (two patients). There was a marked improvement in renal function in eight patients. Two patients with dialysis-dependent renal failure recovered renal function, although in one patient this was transient and she required further dialysis 4 months later. Two other patients progressed to dialysis at 3 months and 1 year respectively. Four patients died, one remains dialysis-dependent, and four continue to have good renal function at 5 year follow-up (median creatinine 148.5 mumol/l, range 120-193 mumol/l). One patient was lost to follow-up at 5 years. FSNGN should be considered in all patients with RA and renal impairment, proteinuria and/or microscopic haematuria. This diagnosis appears to be more likely in patients with clinical extrarenal vasculitis, bone erosions or who are seropositive. In these cases, an urgent renal biopsy is indicated.

Adult↗
PubMed1996

Factors influencing plasma lipid profiles including lipoprotein (a) concentrations in renal transplant recipients.

Fasting plasma cholesterol, triglycerides, high-density lipoprotein (HDL) and apoprotein (apo) B were elevated in 214 nondiabetic renal transplant recipients when compared to a reference group. Apo (a) was slightly but not significantly lower in transplant recipients (median 118 mg/dl, range 16-1680 vs 130 mg/dl, 10-1176) and this difference could be predicted from Lp (a) isoform analysis. Cholesterol, triglyceride, apo B and apo (a) concentrations correlated negatively with creatinine clearance but none of these parameters showed a significant association with proteinuria. Patients treated with steroids had higher plasma HDL concentrations than those receiving cyclosporin monotherapy (P < 0.01). The use of diuretics was associated with raised triglycerides (P < 0.001) and cholesterol (P < 0.01) and with reduced HDL (P < 0.01) whilst patients receiving beta-blockers had significantly higher triglycerides (P < 0.01) and lower HDL levels (P < 0.02). In multiple regression analysis, age (P < 0.01), creatinine clearance (P < 0.05) and diuretic therapy (P < 0.005) were independent risk factors for increased cholesterol whilst apo (a) levels correlated negatively with creatinine clearance (P < 0.005). These results suggest that impaired renal function, steroids and non-immunosuppressive drugs contribute to lipid abnormalites in renal transplant recipients.

Adrenergic beta-Antagonists↗
PubMed1996

Lipid peroxidation contributes to hydrogen peroxide induced cytotoxicity in renal epithelial cells.

We have examined the role of lipid peroxidation in the cytotoxicity of H2O2 in OK cells containing markedly differing amounts of cell membrane polyunsaturated fatty acids (PUFA). In OK cells grown in a serum free medium, PUFA were undetectable. The membranes of these cells contained predominantly oleic, stearic and palmitic acids. When cultured in medium containing 10% calf serum, OK cells contained measurable amounts of PUFA [linoleic (5 +/- 1%) and arachidonic acids (8 +/- 1%)]. When the serum containing medium was supplemented with 60 mM linoleic acid, the membrane content of both linoleic (21 +/- 1%) as well as arachidonic acid (15 +/- 1%) as substantially increased. The severity of injury induced by H2O2 in OK cells was substantially altered by the PUFA content of the cell membrane. Exposure of OK cells to 1.25 mM H2O2 for one hour resulted in more cell death (determined by a trypan blue assay) in cells grown in serum supplemented with linoleic acid with "normal" PUFA content (90 +/- 2%) than in cells with "reduced" levels of PUFA grown in unsupplemented calf serum (81 +/- 3%). Cells gown in defined, serum free medium with undetectable levels of PUFA suffered the least H2O2-induced lethal cell injury (47 +/- 8%). Comparable differences in the cytotoxicity of H2O2 among cells with differing PUFA content were found using a clonogenic assay of cell viability. Malondialdehyde (MDA) accumulation induced by 1.25 mM H2O2 was greater in cells with "normal" PUFA content (702 +/- 103 pM/microgram cell DNA/hr) than in cells with "reduced" PUFA (328 +/- 112 pM/100 microgram DNA/hr) and was undetectable in cells grown in defined, serum free medium. In summary, the content of PUFA of cells in culture is profoundly influenced by culture conditions. Our data provide novel and direct evidence that peroxidation of cell membranes contributes directly to the severity of cell injury and death induced by H2O2.

Animals↗
PubMed1996

Effects of omega-3 fatty acids on complement-mediated glomerular epithelial cell injury.

To define the mechanisms by which fish oil protects rats with passive Heymann nephritis (PHN) from proteinuria in vivo, we investigated whether omega-3 fatty acid substitution of glomerular epithelial cells (GEC) in culture alters their susceptibility or response to complement-mediated sublethal injury. The results show that GECs can be cultured under conditions that effectively incorporate omega-3 or omega-6 fatty acids into membrane phospholipids without causing toxicity. Under these conditions, sublethal injury with anti-Fx1A and C5b-9 stimulated a 6.6-fold increase in TxA2 production by GECs substituted with arachidonic acid (AA, omega-6) but no increase was detected in eicosapentaenoic acid (EPA, omega-3) substituted cells. Sublethal cell membrane injury was of equal severity in both groups as measured by the release of preloaded biscarboxyethyl carboxyfluorescein and by the transepithelial flux of albumin. In addition, omega-3 and omega-6 fatty acid substituted cells showed similar increases in diacylglycerol mass in response to sublethal injury by C5b-9, suggesting that omega-3 incorporation did not limit phospholipid (PL) hydrolysis by PLC. From this we can conclude that the protective effect of fish oil in PHN does not appear to result from the preservation of GEC integrity but is likely related to changes in the production of lipid mediators.

Animals↗
PubMed1995

Molecular genetic diagnosis of von Hippel-Lindau disease in familial phaeochromocytoma.

Inherited predisposition to phaeochromocytoma is seen in multiple endocrine neoplasia type 2 syndromes, von Hippel-Lindau (VHL) disease, and neuro-fibromatosis type 1. In addition familial phaeochromocytoma alone has been reported. To investigate the genetic basis for familial phaeochromocytoma alone, we screened three affected kindreds for mutations in the RET proto-oncogene and the VHL tumour suppressor gene. We did not detect MEN 2 associated RET mutations in any family, but missense VHL gene mutations (V155L and R238W) were identified in two kindreds with no clinical evidence of VHL disease. Patients with familial, multiple, or early onset phaeochromocytoma should be investigated for germline VHL and RET gene mutations as the molecular diagnosis of multisystem familial cancer syndromes enables appropriate counselling and screening to be provided.

Adolescent↗
PubMed1995

Fish oil ameliorates renal injury and hyperlipidemia in the Milan normotensive rat model of focal glomerulosclerosis.

Rats of the Milan normotensive rat strain (MNS) spontaneously develop severe proteinuria and excessive glomerular thromboxane (Tx)A2 production at a young age. These abnormalities are accompanied by podocyte alterations, progressive focal glomerulosclerosis (FGS), and interstitial fibrosis, resembling human FGS. Since it has been shown that pharmacologic Tx-synthase inhibition protects MNS rats from these changes, it was hypothesized that a fish oil (FO) enriched diet, by enhancing TxA3 production instead of TxA2, might afford similar protection, compared with diets enriched in safflower oil (SO) or lard (LD). Rats were pair-fed 11% fat diets from age of 1 to 11 months. Glomerular TxA2 at 11 months was significantly lower in PO-fed rats than in SO- and LD-fed rats (11 +/- 3.0, 69 +/- 3.0, 59 +/- 19.0 nanograms per min/mg, respectively; P < 0.001). At 3 months, urinary albumin excretion was similar among the groups. Over the course of the study, rats fed FO developed significantly less albuminuria than the SO and LD groups (P < 0.001 by analysis of variance for repeated measures), such that the values at 11 months were 25 +/- 5.8, 49 +/- 8.7, and 68 +/- 13.0 mg/24h, respectively. Serum cholesterol and triglycerides were also significantly lower in FO-fed rats than in SO- and LD-fed rats. The extent of FGS was similar in the three groups, but FO-fed rats had less interstitial injury than the other groups. It was observed that a fish-oil diet substantially alleviated albuminuria, normalized nephrotic hyperlipidemia, and reduced interstitial injury, but did not prevent the development of FGS in the MNS model.

Albuminuria↗
PubMed1994

Lipid abnormalities in the nephrotic syndrome: causes, consequences, and treatment.

Hyperlipidemia so commonly complicates heavy proteinuria that it has come to be regarded as an integral feature of the nephrotic syndrome (NS). Characteristically, total plasma cholesterol and triglyceride levels are elevated, as are very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) cholesterol. Although high-density lipoprotein (HDL) concentrations may be normal, HDL subtypes are abnormally distributed, with a reduction of HDL2 and an increase in HDL3. In addition, lipoprotein (a) [Lp (a)] levels may be elevated. The mechanisms underlying these abnormalities are multifactorial, involving both increased rates of lipoprotein synthesis and defective clearance and catabolism of circulating particles. Although recent dietary and therapeutic studies have demonstrated that nephrotic hyperlipidemia can be effectively treated, the need for such intervention has not been clearly established. This pattern of lipoprotein abnormality is associated with an increased risk of cardiovascular disease in the general population, and several studies have suggested that nephrotic individuals are more likely to develop atherosclerosis. However, no prospective trials have evaluated the relationship between deranged lipid metabolism and coronary or cerebral artery disease in patients with NS. In addition, although recent experimental studies suggest that lipid abnormalities may accelerate renal injury and that lipid-lowering agents may protect renal function, there is little current evidence to suggest that such intervention is of value in preserving residual renal function in humans. Further studies are clearly required to assess the potential long-term benefits of lipid-lowering intervention in individuals with NS. In the meantime, based on data generated from other population groups, a rational approach to the clinical management of hyperlipidemia in these patients is presented.

Animals↗
PubMed1994

Oxidation of low density lipoprotein by mesangial cells may promote glomerular injury.

Low density lipoprotein (LDL) deposition and local oxidation play a key role in the pathogenesis of atherosclerosis and may likewise contribute to glomerular injury. These studies were designed to determine whether cultured human mesangial cells oxidize homologous LDL and to compare the effects of unmodified and oxidized lipoprotein on cell proliferation, viability and eicosanoid production. Cell-mediated lipoprotein oxidation was demonstrated and could be suppressed by oxygen free radical scavengers and inhibitors of arachidonic acid metabolism. When incubated with cells, oxidized LDL (Ox-LDL) at concentrations up to and including 100 micrograms/ml reduced 3H-thymidine incorporation without causing cytotoxicity as assessed by lactate dehydrogenase release. Under the same conditions there was a concentration-dependent increase in the synthesis of prostaglandins E2,6-keto-PGF1 alpha and thromboxane B2. In contrast, unmodified LDL enhanced DNA synthesis at concentrations less than 40 micrograms/ml and had little effect on eicosanoid production. These results demonstrate that exogenous oxidized LDL inhibits mesangial cell proliferation and increases eicosanoid synthesis. Unmodified lipoprotein can be directly oxidized by these cells through mechanisms that involve generation of oxygen free radicals.

Cell Division↗
PubMed1994

Butterfat absorption--a valuable screening test in malabsorption.

The diagnosis of intestinal malabsorption is difficult to make without the use of specific tests such as endoscopic retrograde cholangiopancreatography (ERCP) or duodenal biopsy which are invasive and potentially hazardous. Faecal fat estimation or C14 Triolein breath tests have limitations as screening tools are time consuming and expensive. The butterfat absorption test (BFAT) is, in contrast, a simple, quick and cheap test for fat malabsorption. We have assessed the performance of this test in a blinded retrospective study of all such procedures performed in a teaching hospital over an 8 year period. One hundred and fourteen cases of suspected malabsorption had one or more butterfat tests. These were divided into absorbers and malabsorbers without knowledge of the butterfat test results. We found the butterfat test to have a sensitivity of 88% and a specificity of 94% using a cut-off of 20 light-scattering intensity units to discriminate normal from abnormal tests. At this level, predictive values are 91% for a positive result and 92% for a negative. These results are similar to those reported with the C14 Triolein breath test and adjusted faecal fats. We conclude that the butterfat test is a simple, cheap and effective screening test in the diagnosis of malabsorption.

Adolescent↗