Role of iron in the tubulo-interstitial injury in nephrotoxic serum nephritis

Role of iron in the tubulo-interstitial injury in nephrotoxic serum nephritis. We studied the possibility that tubule fluid iron could be involved in the pathogenesis of the tubulo-interstitial injury associated with primary glomerular disease. Tubule fluid iron is determined by the magnitude of the glomerular leak for transferrin and the iron saturation of transferrin. To minimize tubule fluid iron in an experimental model of glomerulonephritis, iron deficiency was induced in rats prior to the induction of nephrotoxic serum nephritis. Iron deficiency did not effect the development of glomerular disease as determined by proteinuria, but had a marked effect on preventing the development of tubulo-interstitial disease and renal functional deterioration. There was also a strong correlation between the amount of functional deterioration and extent of tubulo-interstitial disease and urinary iron excretion in both the control and iron deficient animals. It is proposed that injury results from iron being dissociated from transferrin at the more acid pH of the tubule fluid. Iron, a transition element, is able to catalyze the Haber-Weiss reaction with the formation of free hydroxyl radicals which causes renal tubule cell injury. This tubulo-interstitial injury is the major determinate of progressive renal functional deterioration in this experimental model of glomerulonephritis

Unified Homogenization Theory for Magnetoinductive and Electromagnetic Waves in Split Ring Metamaterials

A unified homogenization procedure for split ring metamaterials taking into account time and spatial dispersion is introduced. The procedure is based on two coupled systems of equations. The first one comes from an approximation of the metamaterial as a cubic arrangement of coupled LC circuits, giving the relation between currents and local magnetic field. The second equation comes from macroscopic Maxwell equations, and gives the relation between the macroscopic magnetic field and the average magnetization of the metamaterial. It is shown that electromagnetic and magnetoinductive waves propagating in the metamaterial are obtained from this analysis. Therefore, the proposed time and spatially dispersive permeability accounts for the characterization of the complete spectrum of waves of the metamaterial. Finally, it is shown that the proposed theory is in good quantitative and qualitative agreement with full wave simulations.Comment: 4 pages, 3 figure

Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

Background: Experimental and clinical data suggest that reducing inflammation without affecting lipid levels may reduce the risk of cardiovascular disease. Yet, the inflammatory hypothesis of atherothrombosis has remained unproved. Methods: We conducted a randomized, double-blind trial of canakinumab, a therapeutic monoclonal antibody targeting interleukin-1β, involving 10,061 patients with previous myocardial infarction and a high-sensitivity C-reactive protein level of 2 mg or more per liter. The trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. RESULTS: At 48 months, the median reduction from baseline in the high-sensitivity C-reactive protein level was 26 percentage points greater in the group that received the 50-mg dose of canakinumab, 37 percentage points greater in the 150-mg group, and 41 percentage points greater in the 300-mg group than in the placebo group. Canakinumab did not reduce lipid levels from baseline. At a median follow-up of 3.7 years, the incidence rate for the primary end point was 4.50 events per 100 person-years in the placebo group, 4.11 events per 100 person-years in the 50-mg group, 3.86 events per 100 person-years in the 150-mg group, and 3.90 events per 100 person-years in the 300-mg group. The hazard ratios as compared with placebo were as follows: in the 50-mg group, 0.93 (95% confidence interval [CI], 0.80 to 1.07; P = 0.30); in the 150-mg group, 0.85 (95% CI, 0.74 to 0.98; P = 0.021); and in the 300-mg group, 0.86 (95% CI, 0.75 to 0.99; P = 0.031). The 150-mg dose, but not the other doses, met the prespecified multiplicity-adjusted threshold for statistical significance for the primary end point and the secondary end point that additionally included hospitalization for unstable angina that led to urgent revascularization (hazard ratio vs. placebo, 0.83; 95% CI, 0.73 to 0.95; P = 0.005). Canakinumab was associated with a higher incidence of fatal infection than was placebo. There was no significant difference in all-cause mortality (hazard ratio for all canakinumab doses vs. placebo, 0.94; 95% CI, 0.83 to 1.06; P = 0.31). Conclusions: Antiinflammatory therapy targeting the interleukin-1β innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering. (Funded by Novartis; CANTOS ClinicalTrials.gov number, NCT01327846.

Aluminum transfer during hemodialysis

Aluminum transfer during hemodialysis. Aluminum concentrations were measured in plasma and urine of normal subjects and chronic hemodialysis patients by using flameless atomic absorption spectrophotometry. Plasma aluminum averaged 7 µg/liter in 13 normal subjects, who excreted an average of 13 µg/day. Predialysis plasma concentrations in 16 patients on low aluminum dialysate (study A) averaged 58 µg/liter, with a postdialysis mean of 63 µg/liter (P < 0.02). Urinary aluminum excretion averaged 9 µg/day during the longest interdialysis interval. Nineteen patients using high aluminum dialysate (stuby B-1) had mean plasma concentrations of 168 predialysis and 265 µg/liter postdialysis (P < 0.001), and they excreted 48 µg/day of aluminum (P < 0.01 vs. study A). After two months of dialysis with low aluminum dialysate (study B-2), 14 patients were restudied. Predialysis aluminum concentration averaged 93, and postdialysis, 114 µg/liter (P < 0.05). Both pre- and postdialysis plasma levels differed significantly among the three groups. During study B-2, aluminum excretion averaged 19 µg/day, significantly less than study B-1 (P < 0.01). One patient was dialyzed for 60min with dialysate containing 128 µg/liter aluminum, and for the subsequent 140min, with 3 µg/liter aluminum dialysate. Plasma aluminum before dialysis was 43 µg/liter. Values across the dialyzer at 15min were 76 and 195 µg/liter at 60min, 148 and 205 µg/liter and at 200min, 110 and 114 µg/liter. We conclude that significant amounts of aluminum can be transferred to plasma during dialysis if dialysate contains virtually any aluminum since aluminum is bound to a nondialyzable plasma constituent. The binding also precludes the removal of aluminum from the patient during dialysis.Transfert d'aluminium au cours de l'hémodialyse. Les concentrations d'aluminium ont été measurées dans le plasma et l'urine de sujets normaux et de malades soumis à l'hémodialyse itérative par spectrophotométrie d'absorption atomique sans flamme. La concentration plasmatique est en moyenne de 7 µg/litre chez 13 sujets normaux qui excrètent une moyenne de 13 µg/jour. La concentration plasmatique avant la dialyse chez 16 malades pour lesquels un dialysat pauvre en aluminium est utilisé (étude A) est en moyenne de 58 µg/litre. Après la dialyse la moyenne est de 63 µg/litre (P < 0,02). L'excrétion urinaire d'aluminium est en moyenne de 9 µg/jour au cours de l'intervalle le plus long entre les dialyses. Dix neuf malades pour lesquels un dialysat riche en aluminium est utilisé (étude B-1) ont des concentrations plasmatiques moyennes de 168 avant la dialyse et 265 µg/litre après la dialyse (P < 0,001). Ils excrètent 48 µg/jour (P < 0,01 par rapport à l'étude A). Quatorze malades ont été étudiés à nouveau après deux mois de dialyse avec un dialysat pauvre en aluminium (étude B-2). Les concentrations plasmatiques sont de 93 avant et 114 µg/litre après la dialyse (P < 0,05). Les concentrations plasmatiques, aussi bien celles d'avant que celles d'après la dialyse, sont significativement différentes dans les trois groupes. Au cours de l'étude B-2, l'excrétion urinaire est en moyenne de 19 µg/jour, significativement moins qu'au cours de l'étude B-1 (P < 0,01). Un malade a été dialysé pendant 60min avec un dialysat contenant 128 µg/litre d'aluminium puis, pendant les 140min suivantes, avec un dialysat contenant 3 µg/litre, La concentration plasmatique d'aluminium avant la dialyse était de 43 µg/litre. Les valeurs de part et d'autre du dialyseur étaient de 76 et 195 µg/litre à 15min, 148 et 205 µg/litre à 60min, 110 et 114 µg/litre à 200min. Nous concluons que des quantités non négligeables d'aluminium peuvent être transférées vers le plasma au cours de la dialyse si le dialysat contient si peu que ce soit d'aluminium du fait que celui-ci est lié à une fraction plasmatique non dialysable. Cette liaison empêche aussi de soustraire de l'aluminium au malade au cours de la dialyse