Correction of uremic iron deficiency anemia in hemodialyzed patients: a prospective study.

This prospective study was designed to evaluate the eventual correction of anemia and iron status in 39 iron-deficient uremics starting hemodialysis. Nine patients (control group) had no iron supplementation, 10 had oral ferrous iron, and 20 were treated with intravenous iron gluconate. Follow-up periods were 12 months for the control group and 26 months for patients treated with oral or intravenous iron. No patient was treated with erythropoietin. At zero time, all patients were anemic (Hb <78 g/l) and showed signs of severe iron deficiency, diagnosed on the basis of depleted bone marrow iron stores, reduced hemoglobin iron, and transferrin saturation <21%. The hemoglobin levels, observed in patients of the control and the oral iron groups at the end of the follow-up periods, were not significantly different from those detected at zero time. In contradistinction, patients treated with intravenous iron showed after 26 months of follow-up a significant increase of blood hemoglobin values, reaching a mean value of 126 g/l. So far, this evidence supports both the concept that iron absorption is compromised in chronic uremics and that the parenteral way is the more effective route for iron replacement in this specific group of patients.

Treatment of surgical and non-surgical septic multiorgan failure with bicarbonate hemodialysis and sequential hemofiltration.

OBJECTIVE: Hospital mortality of patients with septic multiorgan failure (MOF) is still around 95%. The present study investigates whether this high mortality could be significantly reduced by the addition of sequential hemofiltration (SH) with bicarbonate hemodialysis (HD) to the currently used life supportive measures. DESIGN: 35 (18 surgical and 17 nonsurgical) patients, with 3 or more organ failures, had daily sessions of zero balance SH, for periods ranging from 2-22 days. MEASUREMENTS AND RESULTS: SH induced significant improvement of PaO2/100 FIO2, Apache II score, MAP, as well as blood chemistry in survivors. Dying patients had less marked improvement of blood oxygenation, non-significant changes in other variables, in addition to low MAP before and after SH, as well as marked hemodynamic unstability during the procedure. The observed hospital mortality was 38% for the surgical group, and 35.3% for the medical patients (n.s.). CONCLUSIONS: Mortality observed in this retrospective, uncontrolled study was significantly lower than that currently observed with conventional supportive therapy, with or without the addition of other forms of blood purification, e.g. CAVH and CAVHD. This improvement in results appears to be related to the property of SH to completely clear 90% of the blood from mediators of inflammation in only one passage through the hemofilter, and to better tolerance of HD done using bicarbonate buffer. A definite evaluation of this technique will be eventually reached by a programmed, appropriate sample size study, which is out of reach for one individual ICU.

Loss of microvascular negative charges accompanied by interstitial edema in septic rats' heart.

We studied the effect of Gram-negative sepsis on negative charges of heart capillaries and myocardial cells. We used a rat model of multiorgan failure, with ruthenium red (RR) and polyethyleneimine (PEI) as cationic binding tracers. Twenty-four hours after induction of sepsis, negative charges had decreased in glycocalyx and basement membrane of myocardial capillary endothelial cells. There were substantial amounts of interstitial edema. Density of anionic charges in the sarcolemmal glycocalyx complex of cardiac cells was markedly reduced. Myocardial cells' mitochondria consistently showed morphologic changes, whose severity ranged between stages II and IV C of Trump. Thirteen days after induction of sepsis, capillary endothelial and myocardial cells had recovered almost completely and showed no intracellular edema. Gram-negative sepsis caused a significant reduction in negative charges normally present in the microvascular wall as well as on myocardial cells. Consequently, several membranes limiting the various compartments of heart tissue lost their structural integrity. This morphometric data could explain the development of protein-rich interstitial edema and defective cell volume regulation observed in cardiac muscle of endotoxin-shocked animals. This myocardial edema may be at the origin of the cardiac dysfunction observed in both experimental and human septic shock.

Protamine sulfate induces enhanced peritoneal permeability to proteins.

We present a direct link between the neutralization of anionic sites by intraperitoneal protamine and a rise in protein passage to the peritoneal cavity during isosmotic peritoneal dialysis in rabbits. Each experiment included two 1-hour exchanges. No drugs were added in the first exchange. In group A (control) there were no drugs in the second hour either. In group B, protamine (50 micrograms/ml) was added to the second exchange volume. In group C, protamine and heparin (50 U/ml) were added. In groups A and C, appearance curves of metabolites during the first (baseline) and the second (experimental) hours were not statistically different. In group B, differences for urea, glucose and uric acid were not significant, but they were highly so for protein (increase of 100%, p less than 0.01). Transperitoneal passage of albumin is substantially enhanced by protamine. Neutralization of protamine with heparin prevents this, showing that availability of anionic sites is the crucial limiting factor. Protamine did not significantly affect the transfer of small neutral molecules.

Anionic fixed charges in the fenestrated capillaries of the mouse mesentery.

Previous studies showed the existence of submesothelial fenestrated capillaries in the human parietal and rabbit diaphragmatic peritoneum, as well as in the mouse mesentery. The present study demonstrates the presence of electronegative fixed charges at the luminal aspect of endothelial cells, as well as long the subendothelial basement membrane of the fenestrated capillaries of the mouse mesentery. This situation will eventually preclude the transfenestral passage of anionic plasma proteins. On the other hand, fenestrated capillaries are much more permeable to water and small-molecular-size solutes than those of the continuous type. Therefore, the high hydraulic conductivity of fenestrae may well imply that a substantial part of water and small solutes leave the blood compartment through the fenestral channels.

Loss of mesothelial electronegative fixed charges during murine septic peritonitis.

Previous studies showed that murine septic peritonitis induced a substantial reduction of the anionic site density distribution in mesenteric and diaphragmatic microvessels. The present study shows that acute experimental septic peritonitis induces a severe reduction of the anionic site density distribution along the submesothelial basement membrane. Five days after induction of peritonitis, there was a partial recovery of anionic sites which even at 13 days was not completed. This observation suggests that the increased protein losses observed during peritonitis are the consequence of increased microvascular and mesothelial permeability to anionic plasma proteins secondary to neutralization and/or disappearance of the anionic sites located in the microvascular wall and in the mesothelial layer.

Fenestrated capillaries in mice submesothelial mesenteric microvasculature.

This study demonstrates the existence of fenestrated capillaries in the microvascular bed of mice mesentery. The 26.6% incidence of fenestrated capillaries observed in this study is similar to that found in rabbit diaphragmatic peritoneum. Fenestral diameters are too large to be identified as the large pore of Pappenheimer's theory. They appear to be too frequent to become the predicted large pore. Peritoneal permeability should be analyzed on the basis that molecular transfer occurs through multiple ways.

Decreased density distribution of mesenteric and diaphragmatic microvascular anionic charges during murine abdominal sepsis.

Pulmonary edema of sepsis is a consequence of increased transmural conductance for water and proteins at the level of lung microvessels induced by vasoactive endogenous mediators, liberated after activation of complement by bacterial endotoxins. Intermittent opening of interendothelial junctions at the level of post-capillary venules has been implicated as being the pathway for the leaking plasma proteins and water. Microvascular basement membranes and endothelial cell surfaces have fixed anionic charges (AS) which prevent the escape of plasma proteins from the circulation as well as the adhesion of blood cells to the luminal endothelium. The density distribution of these AS was substantially reduced in visceral and systemic microvessels during murine abdominal sepsis. This observation suggest that MOF secondary to sepsis is the consequence of a severe and generalized alteration of the microvascular electronegative charge, induced by liberation of inflammatory mediators.

Ruthenium-red-stained anionic charges of rat and mice mesothelial cells and basal lamina: the peritoneum is a negatively charged dialyzing membrane.

The peritoneum has been classically considered to be an inert passive membrane. Previous studies demonstrated the presence of fixed anionic charges at the level of the peritoneal microvasculature and the subserosal interstitium. The present study describes the selective distribution of fixed anionic charges in the mesothelial cell plasmalemma and organelles as well as in the submesothelial basal lamina of rat and mice visceral, parietal and diaphragmatic peritoneum. These data support the idea that the peritoneum should be considered a negatively charged biological dialyzing membrane with selective capabilities. Therefore, transperitoneal transfer of charged solutes cannot be analyzed just on the basis of their molecular weight, size and shape.

Ruthenium-red-stained polyanionic fixed charges in peritoneal microvessels.

This study shows that the luminal surface of peritoneal microvascular endothelium, coated pits and coated vesicles are all negatively charged, unlike the limiting membrane of pinocytotic vesicles and transcellular channels. Our findings suggest that these cellular organelles have different functions as well as a different chemical composition. Anionic sites were observed along the subendothelial and subperithelial basal laminae of peritoneal capillaries and post capillary venules, respectively. Electric charge is a new parameter to be considered when analyzing transperitoneal transfer of charged macromolecules.

Hemofiltration in septic ARDS. The artificial kidney as an artificial endocrine lung.

Twenty-four patients with high microvascular permeability pulmonary edema were initially treated by means of conventional supportive therapy for 1-12 days. Continued deterioration was treated by predilutional hemofiltration and induced a dramatic improvement in 22/24 patients. Survival was 92%. Sieving coefficients for autacoids and middle molecular weight vasoactive peptides involved in the development of high microvascular permeability pulmonary edema were higher than 0.88 indicating that clearing from blood of these peptides during one pass through the hemofilter is similar to that obtained during one pass through the pulmonary normal microvasculature. Hemofiltration seems to be a significant breakthrough in the treatment of ARDS secondary to severe sepsis.