Adam Linton--the man.
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History, 20th Century↗
Biomedical subjects
W F Clark
Publications and source records attributed to W F Clark.
Treatment of lupus nephritis: immunosuppression, general therapy, dialysis and transplantation.
The treatment of patients with clinical lupus nephritis is based on a combination of our understanding of the natural history of the disease, a large number of anecdotal reports, and a small number of studies which demonstrate statistical treatment benefits. This review is directed towards the treatments (immunosuppressive, general therapy, and end-stage renal failure management) which have been demonstrated to have been, or not to have been, beneficial. Although the prognosis of patients with lupus nephritis is undergoing continuous improvement, this may relate as much to changes in general treatment measures as to specific immunosuppressive schedules.
Diet↗
Abrogation of MRL/lpr lupus nephritis by dietary flaxseed.
A diet supplemented with flaxseed, rich in alpha-linolenic acid and plant lignans (the latter, potent platelet-activating factor receptor antagonists), was tested in a murine model of lupus nephritis. MRL/lpr female mice (n = 25) were fed 15% flaxseed diet for 14 weeks commencing at 10 weeks of age. As controls, 30 MRL/lpr mice received a standard rodent diet without flaxseed. Isotope-glomerular filtration rate (14C-inulin clearance) was measured at 9, 16, and 24 weeks of age. Proteinuria was assessed at 2-week intervals. Spleen lymphocyte proliferation, quantitated by DNA analysis, was evaluated using flow cytometry at 9, 13, 19, and 21 weeks of age. Mortality was recorded throughout the study. Glomerular filtration rate at 16 weeks was greater in flaxseed-fed mice (0.15 +/- 0.03 mL/min) compared with controls (0.06 +/- 0.04 mL/min; P = 0.01). The onset of proteinuria (Albustix, Ames Division, Miles Laboratories, Rexdale, Ontario, Canada; > or = 2+) was delayed by 4 weeks in the flax-treated mice. The percentage of flaxseed-fed mice with proteinuria was lower than the control mice up to 21 weeks of age (39% v 58%; P = 0.01). Spleen lymphocyte proliferation (percentage of cells in S-phase) at 13 weeks of age was significantly higher in the control group (22.9 +/- 5.0, P = 0.01) but not in the flaxseed group (17.2 +/- 4.9) compared with baseline (9 weeks of age) values (13.0 +/- 3.5). Mortality was lower in the flaxseed-fed mice versus the control mice (assessed by Mantel-Haenszel (log-rank) test; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Fish oil in lupus nephritis: clinical findings and methodological implications.
Our objective was to determine the effects of fish oil on renal function, symptoms, and serum lipids in patients with lupus nephritis. A double-blind, randomized crossover trial of fish oil versus placebo (olive oil) was done on 26 patients with confirmed systemic lupus; 21 completed the study. Intervention was fish oil or placebo, 15 g/day, for one year followed by a 10 week wash-out period, and then the reverse treatment for one year. At baseline and six month intervals, we measured platelet membrane fatty acids, indices of renal function, a disease activity index, serum lipid levels, blood pressure, serum viscosity and red cell flexibility. We found that platelet membrane phospholipids were uniformly affected by fish oil supplementation (P < 0.001) but with significant carry-over effects despite a 10 week wash-out period. Glomerular filtration rate and serum creatinine were not affected. A non-significant reduction in mean (SE) 24-hour proteinuria occurred, from 1424.1 mg (442.7) on placebo to 896.7 mg (352.2) on fish oil (P = 0.21). Fish oil lowered serum triglycerides from 1.89 (0.25) mmol/liter to 1.02 (0.11) mmol/liter (P = 0.004). VLDL cholesterol decreased markedly whether patients initially received fish oil or placebo (P = 0.004). The size of the reduction was affected by the order of treatment (P = 0.03), but parallel comparisons were significant before the crossover (P = 0.0006). With the possible exception of bleeding time, no other treatment effects were shown with fish oil. However, treatment order effects were seen in urinary IgG excretion (P = 0.03), whole blood viscosity (P < 0.0001), red cell flexibility (P = 0.004), and bleeding time (P = 0.06). In conclusion, one year of dietary supplementation with fish oil in patients with stable lupus nephritis did not improve renal function or reduce disease activity, but did alter some lipid parameters. Hitherto unreported carry-over effects and treatment order effects caused by the olive oil created a risk of type II error, and bear methodologic consideration in the design of future studies.
Adult↗
Dietary protein restriction versus fish oil supplementation in the chronic remnant nephron model.
Dietary protein restriction and fish oil supplementation (MaxEPA) have been reported to have favourable effects on the remnant nephron model. In the present study female Munich-Wistar rats underwent 5/6 renal ablation (60 rats) or sham surgery (20 rats). The renal ablation rats were randomized one week post-surgery to receive a diet that contained either regular laboratory diet (RLD), 6% low protein diet (LPD) or 24% fish oil diet (FOD) supplementation. Mortality rates at 10 and 20 weeks post-surgery were not different amongst the RLD, LPD or FOD renal ablation cohorts. However the G.F.R. was significantly preserved in the FOD and LPD versus the RLD renal ablation rat groups. Both the LPD and FOD decreased albuminuria and gammaglobulinuria but LPD was more effective. Both dietary interventions prevented glomerulosclerosis but only LPD significantly reduced mesangial expansion. The FOD diet prevented intraglomerular fibrin formation and the LPD had no effect. The dyslipidemia noted at 20 weeks in the renal ablation group was significantly abrogated by both FOD and LPD, although only LPD prevented the heavy proteinuria. The LPD rats gained significantly less weight than the FOD and RLD cohorts. FOD exerted a significantly greater effect on blood pressure reduction than the LPD and also produced significant changes in the renal tissue phospholipids. These results indicate that protein restriction and fish oil supplementation preserve renal structure and function in the remnant nephron model but have different effects on mechanisms known to be co-factors in the progressive renal injury.
Animals↗
Omega-3 fatty acid supplementation in primary nephrotic syndrome: effects on plasma lipids and coagulopathy.
The effect of fish oil dietary supplementation on the dyslipidemia and coagulopathy of seven patients with nephrotic syndrome and hypoalbuminemia due to primary kidney disease was studied. Plasma lipids, platelet aggregation studies, simplate bleeding time, and fibrinogen levels were determined before and after 6 wk of treatment with fish oil (15 g/day of MaxEPA; 2.7 g of eicosapentenoic acid (EPA) and 1.8 g of docosahexenoic acid. Urea kinetics were determined from urine-urea concentration, urinary proteina, and urine volume. A 3-day dietary intake record was obtained from each patient before and after 6 wk of fish oil supplementation. There was no significant dietary change in protein, fat, or carbohydrate intake over the time period of the study. At study end, total triglycerides decreased from 2.98 +/- 1.31 to 2.18 +/- 1.14 mmol/L (P = 0.002), and very low-density lipoprotein-triglycerides decreased from 2.35 +/- 1.34 to 1.28 +/- 1.07 mmol/L (P = 0.01). Low-density lipoprotein (LDL) cholesterol increased from 5.18 +/- 1.74 to 7.35 +/- 2.83 mmol/L (P = 0.005). No significant changes occurred in bleeding time, platelet count, hematocrit, red blood cell flexibility, or whole blood viscosity. Platelet aggregation responses to collagen and arachidonic acid were consistently reduced after treatment, but there was no change in platelet response to ADP. The platelet membrane phospolipids showed a significantly increased incorporation of EPA after the fish oil diet (P = 0.03).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Heparin-induced thrombocytopenia in renal failure.
A 35-year-old patient with symptomatic chronic renal failure secondary to hereditary nephritis underwent heparinization during urgent hemodialysis. Subclavian catheter insertion was complicated by staphylococcal septicemia which precluded Gore-tex graft placement. Arteriovenous fistula failed immediately postoperatively and thrombectomy was required. Heparin-induced thrombocytopenia was suspected and the test was strongly positive. Acetyl salicylic acid (ASA) 40 mg, was used with heparin for dialysis, and there were no episodes of gastrointestinal hemorrhage or access site thrombosis. The use of very low-dose ASA in this setting is reported.
Adult↗
Plasmapheresis and subsequent pulse cyclophosphamide versus pulse cyclophosphamide alone in severe lupus: design of the LPSG trial. Lupus Plasmapheresis Study Group (LPSG).
A group of clinics are collaborating in the Lupus Plasmapheresis Study Group (LPSG) to investigate whether repeated plasmapheresis prior to pulse cyclophosphamide improves the therapeutical results in severe systemic lupus erythematosus (SLE). The underlying rationale is the hypothesis that plasmapheresis 1) eliminates pathogenic autoantibodies and immune complexes and 2) induces compensatory lymphocyte activation via feedback mechanisms between circulating antibodies and their respective clones ("antibody rebound"). It should be possible to utilize this enhanced activity for increased clonal deletion if pulse cyclophosphamide is applied shortly after plasmapheresis. Accordingly, in a randomized study, the LPSG will be comparing the repeated application of pulse cyclophosphamide alone with a treatment involving repeated plasmapheresis prior to the cyclophosphamide pulses in severe SLE. A third arm of the study will be gathering experience with a more intensified procedure. This overview summarizes the most important details of the planned study.
Combined Modality Therapy↗
Dietary lipid modification of renal disorders and ether phospholipid metabolism.
The formation of arachidonic acid derived eicosanoids, including thromboxane A2 and leukotriene B4, as well as platelet-activating factor (1-O-alkyl-2-acetyl-glycerophosphocholine), has been implicated in various renal pathophysiologies. Alteration of the fatty acid composition of membrane phospholipids in platelets, the glomerulus, and inflammatory cells, and of 1-O-alkyl-2-acyl-glycerophosphocholine (platelet-activating factor precursor) can be attained by dietary lipid modifications (e.g., consumption of fish oil containing n - 3 polyunsaturated fatty acids). These changes have been associated with an attenuation in renal disease progression and modifications in the synthesis and actions-interactions of eicosanoids, cytokines, and platelet-activating factors.
Animals↗
Chronic effects of omega-3 fatty acids (fish oil) in a rat 5/6 renal ablation model.
It has been proposed that fish oil dietary supplementation in the chronic rat 5/6 renal ablation model may be either protective or toxic. These conflicting hypotheses were tested in rats who underwent renal ablation or sham surgery. Twenty rats received sham surgery, and 40 received 5/6 renal ablation. All rats were fed a regular laboratory diet up to 1 week postsurgery. At that time, one half of the renal ablation group was provided with an isocaloric diet supplemented with 24% MaxEPA (fish oil), 1% safflower oil, and antioxidants. The renal ablation rats developed hypertension, albuminuria, gammaglobulinuria, and a decline in glomerular filtration rate, which was less in the fish oil group compared with that in the regular laboratory diet group at 10 and 20 wk postsurgery. The fish oil renal ablation rats had significantly less glomerulosclerosis than did the regular laboratory diet renal ablation animals, and no more glomerular fibrin deposition than did the sham controls. The renal ablation regular laboratory diet rats had a significant dyslipidemia at 20 wk which was prevented in the fish oil renal ablation cohort. The fish oil renal ablation rats also demonstrated a significant decline in renal tissue arachidonic acid incorporation and a concomitant increase in eicosapentaenoic acid and docosahexaenoic acid incorporation. The mortality of the renal ablation group was greater than that of the sham controls but not significantly different for the fish oil or the regular laboratory diet groups. These results support the hypothesis that the fish oil diet containing specific antioxidant, vitamin E, and essential fatty acid supplementation is protective in the rat remnant nephron model and prevents the evolution of glomerulosclerosis with associated renal functional impairment, while preserving glomerular filtration.
Animals↗
Comparative efficacy of dietary treatments on renal function in rats with sub-total nephrectomy: renal polyunsaturated fatty acid incorporation and prostaglandin excretion.
The efficacy of dietary intervention with either 6% protein restriction, fish oil or safflower oil was assessed in the remnant nephron model. Female Munich Wistar rats were prefed for one week prior to 5/6 nephrectomy and followed for the ensuing 28 days. Fish oil, safflower oil and protein restriction prevented the gammaglobulinuria but only fish oil lessened the albuminuria in this model. The remnant nephrons of the fish oil treated rats contained less arachidonic acid and greater quantities of eicosapentaenoic and docosahexaenoic acid than the safflower oil or lab chow fed control rats. The fish oil, and to a lesser extent the safflower oil, treated animals had a higher ratio of 6 keto PGF1 alpha to TX B2 metabolites in their urine. We suggest these changes may be responsible for the lessening in urine protein excretion. Fish oil feeding was more effective than severe protein restriction or safflower oil dietary supplementation in lessening both the gammaglobulinuria and albuminuria of the remnant nephron model.
6-Ketoprostaglandin F1 alpha↗
Prolongation of acute renal failure in two patients with hemolytic-uremic syndrome due to excessive plasma infusion therapy.
Two children with prototypic hemolytic-uremic syndrome had prolonged acute dialysis-dependent renal failure (74 and 84 days) associated with a state of hyperproteinemia induced by extensive infusion of fresh frozen plasma (283 and 307 units). We believe that the hyperproteinemia prolonged the duration of renal failure. Following cessation of plasma therapy, the hyperproteinemic state reversed, the degree of proteinuria decreased and renal function quickly recovered. Although the pathophysiological mechanism requires further evaluation, we speculate that an alteration in the colloid oncotic pressure and/or aggravation of tubulointerstitial injury due to overload-proteinuria may have increased the duration of renal failure.
Acute Kidney Injury↗
The role of platelets in progressive glomerulosclerosis: mechanisms for intraglomerular platelet activation and pathogenetic consequences.
Purkerson et al. have hypothesized that platelet aggregation and release reactions contribute to the progressive sclerosis of remnant nephrons. The suggested mechanism for platelet activation is disruption of endothelium by the high hydraulic pressures characteristic of remnant nephrons, with platelet exposure to basement membrane collagen. We herein postulate additional mechanisms whereby platelets might be activated in the microcirculation of remnant nephrons: (i) kinetic activation due to high plasma flow rates; (ii) close cell contact due to concentration of blood cells and platelets in the glomerulus; (iii) concentration of protein macromolecules that act as agonists for platelet release; (iv) glomerular release of saturated and monenoic fatty acids that stimulate platelet synthesis of thromboxane A2; (v) glomerular release of membrane-bound pro-coagulant factor, triggering a chain reaction that activates both platelets and the intraglomerular coagulation cascade. Platelet activation could play a pathogenetic role in many of the known derangements of structure and function in remnant nephrons. This paradigm may also be partially applicable to the glomerulosclerosis of diabetes mellitus.
Animals↗
Omega-3 fatty acid dietary supplementation in systemic lupus erythematosus.
The effect of dietary fish oil (Omega-3 fatty acids--eicosapentenoic acid [EPA] and docosahexaenoic acid [DHA] on several mechanisms involved in immune, inflammatory and atherosclerotic vascular disease was determined in 12 subjects with systemic lupus erythematosus (SLE) and nephritis. These out-patients supplemented their usual diet for five weeks with daily doses of 6 g of fish oil, followed by a five-week washout period, then five weeks of 18 g of fish oil daily. The platelet EPA content rose six-fold with the lower and 15-fold with the higher dose of fish oil, and similar changes occurred to the platelet DHA content. The platelet arachidonic acid incorporation was reduced by 16 and 20%, respectively. These changes were associated with a reduction in collagen-induced platelet aggregation and an increase in red cell flexibility and a decrease in whole blood viscosity. Prostacyclin (PGI2) production was unaffected by the fish oil, but PGI3 formation correlated with its administration and dosage. Neutrophil leukotriene B4 release was reduced 78 and 42%, respectively, by the low and higher doses of fish oil. The higher fish oil dose induced a 38% decrease in triglyceride and a 39% reduction in VLDL cholesterol associated with a 28% rise in HDL, cholesterol. The fish oil had no effect on immune complex or anti-DNA antibody titer, albuminuria, intraplatelet serotonin or [14C]-serotonin release from platelets. We conclude that in patients with lupus nephritis, dietary supplementation with fish oil affects the mechanisms involved in inflammatory and atherosclerotic vascular disease.
Adult↗
Polymorphonuclear leukocytes labeled with technetium-99m HMPAO. A potential bone marrow imaging agent.
A case of multifocal avascular necrosis of the bone complicating systemic lupus erythematosis is presented in which the extent of involvement was incidentally identified by Tc-99m HMPAO leukocyte imaging. Leukocytes labeled with Tc-99m HMPAO may be an excellent bone marrow imaging agent.
Adult↗
Effect of cyclosporine on plasma lipids and modification with dietary fish oil.
Hyperlipidemia is an identified risk factor for atherosclerosis in patients following renal transplantation that may be related to previous uremia and various drugs including steroids. Recent evidence has suggested that treatment with cyclosporine may be an independent risk factor for development of hyperlipidemia in some patients. Twenty-four Sprague Dawley rats were given CsA at 30 mg/kg by gavage for 28 days in 1 ml of olive oil or fish oil vehicle, and compared with controls receiving just vehicle. Increases of both triglyceride (233.6%) and cholesterol (50.9%) were observed in olive oil/CsA animals (P less than .01), with no significant change noted with either vehicle alone. An increase of triglyceride from baseline was observed with fish oil/CsA (119%) (P less than .01) but was significantly less than the increase with olive oil/CsA animals (P less than .05). No increase in cholesterol was found in CsA-treated rats using the fish oil vehicle. The mechanisms leading to hyperlipidemia with four weeks of CsA administration in these rats are unknown, but may be related to altered hepatic synthesis. CsA levels were lower in fish oil-treated animals, possibly explaining the difference noted in lipid levels--or, alternatively, reduction of plasma lipoproteins may have altered drug kinetics and CsA binding. This work emphasizes a need for further study of lipids in CsA-treated patients, and advises some caution in the use of lipoprotein-reducing agents in patients using CsA without consideration of the possible effect on free drug levels.
Animals↗
Binding of aggregated immunoglobulins to the human platelet Fc receptors: a mechanism of platelet to platelet bridging.
Aggregated immunoglobulins react with human platelets by occupying the Fc receptors present on their surface, inducing aggregation and the release reaction. We studied the effect of heat aggregated gammaglobulins (HAGG) on ADP-induced aggregation of platelets. We used the minimum concentration of ADP required to induce a reversible aggregation of platelets without any substantial amount of serotonin (14C-5HT) release. EDTA (5 mM) added at the peak of platelet aggregation resulted in rapid deaggregation of these platelets. However, incubation of platelets with HAGG at a dose that did not by itself induce any aggregation or release reaction, followed by ADP addition resulted in an irreversible platelet aggregation of greater magnitude accompanied by a substantial release of 14C-5HT. The addition of EDTA at the peak of platelet aggregation failed to deaggregate these platelets. To determine whether the augmented aggregation response and the inhibition of deaggregation was due to HAGG or a consequence of platelet release products, we used thrombin-degranulated platelets. The augmented aggregation response and the inhibition of deaggregation due to HAGG and ADP could be demonstrated using these platelets. To confirm that the binding of HAGG to the platelet Fc receptors was responsible for these observations, we incubated platelets with an excess of Fc fragments of IgG prior to the addition of HAGG and ADP. This abolished the aggregation response observed previously. From this study we conclude that interplatelet bridging by HAGG renders the platelets hyperaggregable and appears to be a mechanism involved in maintaining platelet aggregates.
Adenosine Diphosphate↗
Spontaneous aggregates of immunoglobulin-G prime the human platelet release reaction induced by close cell contact.
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Adenosine Diphosphate↗