Function of endocrine organs in hemodialyzed patients of long-term erythropoietin therapy.

Endocrine abnormalities in patients with chronic renal failure are well documented. The present study aimed to assess the influence of long-term erythropoietin (EPO) therapy on endocrine abnormalities in hemodialyzed patients. Two groups of hemodialyzed patients, each of which comprised 17 subjects, were examined. The first group was treated by EPO (EPO group) while the second one did not receive this hormone (No-EPO group). A complete biochemical and hormonal check-up was performed before and at the 3, 6, 9, and 12 month points of the study period. Normal values for the estimated parameters were obtained in appropriately selected sex- and age-matched healthy subjects. After EPO therapy, an increase of the hematocrit value from 21.8 +/- 0.9 to 32.6 +/- 0.9% was observed, which was accompanied by a significant decline of plasma ferritin and saturation of transferrin. In patients of the No-EPO group, a significant although less marked rise of the hematocrit value (21.4 +/- 0.4 to 24.2 +/- 0.6%) was also noticed. EPO therapy did not change plasma levels of electrolytes (Na, K, Ca, inorganic phosphate), osteocalcin, creatinine, glucose, and alkaline phosphatase as well as plasma concentrations of calcium-related hormones (PTH, calcitonin, 1,25[OH]2D3), vasopressin, and triiodothyronine. EPO treatment induced a significant decrease in somatotropin, prolactin, follitropin, lutropin, ACTH, cortisol, plasma renin activity, aldosterone, noradrenaline, adrenaline, dopamine, glucagon, pancreatic polypeptide, and gastrin plasma levels and an increase in plasma insulin, estradiol, testosterone, atrial natriuretic peptide, thyrotropin, and thyroxine.(ABSTRACT TRUNCATED AT 250 WORDS)

Urinary excretion of cathepsin B and cystatins as parameters of tubular damage.

The urinary excretion of the lysosomal hydrolases cathepsin B and beta-N-acetylglucosaminidase (beta-NAG) was compared with the tubular activities of these enzymes in remnant kidneys 16 weeks after subtotal nephrectomy (5/6 NX) or unilateral nephrectomy (UNX), as well as in kidneys from diabetic rats. In addition, the urinary excretion of the low-molecular weight protein cystatins, inhibitors of lysosomal cathepsins, was also followed in these animals. The urinary excretion of cathepsin B and beta-NAG was significantly enhanced in all three models of renal disease. The highest excretion rates for these enzymes were found in diabetic animals (cathepsin B: 4-fold; beta-NAG: more than a 10-fold increase over respective controls). In terms of tubular enzyme activities, tissue activities of both hydrolases were reduced in the remnant kidney after 5/6 NX, while in UNX and diabetes only cathepsin B activity was decreased. The urinary excretion of cystatins was enhanced in all three animal models, particularly in 5/6 nephrectomized rats, where a 40-fold increment over control animals was observed. Taken together, these findings indicate that there was severe tubular damage in the remnant kidney after 5/6 NX (reduced tubular enzyme activities, enzymuria and severely compromised tubular protein reabsorption). Furthermore, considerable enzymuria and disturbed protein reabsorption in early diabetes suggest tubular dysfunction before signs of glomerular damage become evident.

Enhanced activity of sympathetic renal nerves in hypertensive patients with unilateral renal ischemia--its relationship to plasma renin activity in renal venous blood.

In 16 hypertensive patients with significant unilateral renal artery stenosis plasma renin activity (PRA) and plasma levels of adrenaline (A), noradrenaline (NA) and dopamine were assessed in arterial blood, renal venous blood of the ischemic (IK) and normally (NK) perfused kidney and in blood withdrawn from the inferior vena cava, distally from the orifices of the renal veins. Plasma levels of A (= 661.8 +/- 187.7 pg/ml) and NA (= 396.3 +/- 72.5 pg/ml) in renal venous blood of the ischemic kidney were significantly greater than in renal venous blood of the normally perfused kidney (A = 123.4 +/- 16.0 pg/ml; NA = 277.2 +/- 55.6 pg/ml) and than in arterial blood (A = 68.44 +/- 8.4 pg/ml; NA = 192.8 +/- 28.9 pg/ml) and inferior vena cava blood (A = 67.8 +/- 7.5 pg/ml; NA = 182.6 +/- 26.8 pg/ml). In contrast to A and NA, plasma D level in renal venous blood of the normally perfused kidney was significantly higher (= 27.9 +/- 4.9 pg/ml) than in renal venous blood of the ischemic kidney (= 14.3 +/- 2.1 pg/ml) and than in arterial blood (= 16.1 +/- 1.9 pg/ml) and in blood of the inferior vena cava (= 16.3 +/- 1.8 pg/ml). A significant positive correlation was found between PRA and plasma levels of A and NA respectively only in renal venous blood of the ischemic kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Improved immunoglobulin production in dialysis patients treated with recombinant erythropoietin.

Improvements in B lymphocyte function have been reported in hemodialysis patients receiving erythropoietin. The present investigation studied whether erythropoietin interferes with B cell function and the mechanisms of this effect. Antibody production by cultured peripheral blood mononuclear cells (PBMC) (7 days) from 15 dialysis patients before and during erythropoietin treatment and from 14 healthy controls was followed. IgG and IgA were formed less in the uremic group than in healthy subjects. After 8 weeks of erythropoietin (hematocrit rose from 19 to 31%) basal IgG formation by PBMC rose from 304 +/- 83 to 566 +/- 49 ng/ml (p less than 0.02), while IgA production rose from 380 +/- 121 to 563 +/- 362 ng/ml (p less than 0.01). IgM production, which appeared to be normal in uremia, remained unchanged during erythropoietin treatment. Production of IgG and IgA stimulated by pokeweed-mitogen was subnormal in uremia, but improved under erythropoietin therapy. To establish whether erythropoietin acted by itself or through correction of the renal anemia, healthy PBMC were directly incubated with 2 U/ml of erythropoietin. Under these conditions production of IgG (+19%), IgA (+28%), and IgM (+32%) was enhanced. Taken together these data indicate a direct stimulant effect of erythropoietin on B lymphocytes in end-stage renal failure.

Effects of volatile anesthetics on cytoplasmic Ca2+ signaling and transmitter release in a neural cell line.

To provide new insights into the effects of volatile agents on the basic regulatory events involved in cytoplasmic free Ca2+ ([Ca2+]i) and stimulus-secretion coupling, the well-characterized clonal rat pheochromocytoma cell line PC12 was chosen as an experimental model. This cell line possesses nicotinic and muscarinic receptors, L-type voltage-operated channels (VOCs), and receptor-operated Ca2+ channels (ROCs). A PC12 variant, defective in nicotinic response, made it possible to study the influx-independent inositol trisphosphate-mediated intracellular Ca2+ release that is triggered by muscarinic receptor stimulation. [Ca2+]i was measured with the fluorescent Ca2+ indicator fura-2. Dopamine and norepinephrine secretion were determined by high-performance liquid chromatography. High K+ and nicotinic-receptor-induced [Ca2+]i increase and catecholamine secretion were inhibited by halothane, enflurane, isoflurane, and methoxyflurane in a dose-dependent manner; half-maximal inhibition (IC50) occurred within the clinically relevant concentration range. The inhibition was reversible after wash-out of anesthetic; was not restricted to dihydropyridine-sensitive L-type VOCs; and could not be overcome by increasing extracellular Ca2+. The inhibitory mechanisms of volatile anesthetics therefore differed from those of classical organic Ca2(+)-channel blockers, a difference also reflected by the differing Hill coefficients found for both substance groups. In contrast, the muscarinic-receptor-evoked internal Ca2+ release remained unimpaired, and secretion even increased under anesthetic exposure. In conclusion, the current study provides evidence that volatile anesthetics depress the Ca2+ influx through at least two independent Ca2+ channels, one of which proved insensitive to the dihydropyridine Ca2(+)-channel blocker nifedipine. This is particularly noteworthy, since dihydropyridine-insensitive N-type VOCs, so far found exclusively in neurons, are assumed to play a dominant role in synaptic transmission, which, although resistant to dihydropyridine inhibition, is effectively blocked by volatile anesthetics.

Evaluation of a new polyamide membrane (Polyflux 130) in high-flux dialysis.

Removal of beta 2-microglobulin has become a major objective of dialysis therapy. The present study was performed to evaluate both compatibility and elimination capacity for beta 2-microglobulin of a newly developed high-flux polyamide membrane (Polyflux 130) during hemodialysis. The degree of leukopenia was moderate (-22%) and comparable with Polysulfone 600 (-25%). C3a desarg generation had a tendency to be lower with the Polyflux 130 membrane, and C5a desarg formation was identical with both types of membranes. As for degranulation of polymorphonuclear leukocytes, plasma elastase levels increased by 209% with Polyflux 130 and by 160% with Polysulfone 600 membranes. Likewise, plasma lactoferrin values rose during hemodialysis by 233% (Polyflux 130) and 160% (Polysulfone 600). The differences between membranes, however, were statistically not significant. There was a sharp drop in the serum levels of beta 2-microglobulin during dialysis with both membranes (Polyflux 130: -46%; Polysulfone 600: -48%). Accordingly, sieving coefficients were calculated to be 0.77 +/- 0.06 for Polyflux 130 and 0.80 +/- 0.06 for the Polysulfone 600 membrane. Both membranes were capable to remove large quantities of beta 2-microglobulin, amounting to 235 +/- 11 and 250 +/- 10 mg/4 h of dialysis for Polyflux 130 and Polysulfone 600, respectively.

Clinical evaluation of a new high-flux cellulose acetate membrane.

One major goal of dialysis therapy has become the removal of beta 2-microglobulin (beta 2-m). The interdialytic elimination of beta 2-m was studied using a newly developed high-flux cellulose acetate (CA) membrane. The results show that high-flux CA dialyzers offer better biocompatibility than classical Cuprophan or high-flux Cuprophan devices, with regard to leukopenia, C3a desarg generation, and elastase release from polymorphonuclear (PMN) leukocytes. Compared to high-flux CA membranes, high-flux PMMA membranes induce less C3a desarg formation but comparable leukopenia. High-flux PMMA membranes, however cause greater leukocyte stimulation than CA as demonstrated by more PMN elastase release during hemodialysis. Using high-flux CA or high-flux PMMA membranes, serum beta 2-m levels decreased 32% during dialysis. Serum beta 2-m dropped 10% with high-flux Cuprophan membranes, but remained unchanged with conventional Cuprophan dialyzers. Sieving coefficients for beta 2-microglobulin (beta 2-m) were virtually zero with classical Cuprophan and 0.66 with high-flux cellulose acetate membranes. High-flux membranes made of Cuprophan and PMMA gave coefficients of 0.25 and 0.45, respectively. This indicates the high removal capacity of the new CA-membrane for substances with high molecular weight. This high-flux CA membrane thus appears to combine a good degree of biocompatibility with a high capacity for beta 2-m removal.

Activation of leukocytes during prolonged physical exercise.

Previous studies have demonstrated an increment of circulating leukocytes and enhanced secretion of interleukin-1 by monocytes and macrophages during physical exercise. In the present study the effect of physical exertion on the activity of polymorphonuclear (PMN) leukocytes was investigated. Following both short-term (running 2,000 meters) and long-term (running 10,000 meters) exertion, phorbol-stimulated chemiluminescence, as an indicator of leukocytic oxygen radical formation and release of leukocytic elastase, as a parameter of degranulation, were determined immediately after running. The number of circulating leukocytes increased both after short-term (+21%) and long-term (+61%) exercise. There was a minor release of PMN elastase following short-term activity causing plasma levels of this compound to rise from 100 +/- 4.0 ng/ml to 116 +/- 12.3 ng/ml. Long-term exercise, on the other hand, induced a significant increase of elastase plasma levels from 107 +/- 9.1 ng/ml to 300 +/- 23.4 ng/ml, suggesting a remarkable release of this proteinase from neutrophils. Based on these findings we conclude that during physical exercise degranulation of PMN leukocytes occurs. Moreover, the fact that phorbol-stimulated chemiluminescence is decreased after running demonstrates an impaired capability of white cells to generate oxygen radicals.

Elimination of low molecular weight proteins during hemofiltration.

In patients on regular dialysis treatment, uremic symptoms (anemia, osteopathy, myopathy, neuropathy, and disorders of carbohydrate, fat, and protein metabolism) may be partly due to an accumulation of low molecular weight (MW) proteins (10,000 to 60,000 daltons). We tested this hypothesis using membranes with a higher permeability than conventional Cuprophan membranes. The primary aim of the study was to test the cutoff of various hemofilters (Cuprophan [Highflux], polyamide [FH 20], cellulose acetate [Duoflux], and polyacrylonitrile [Hospal RP 7 + 8 and Asahi PAN]) under in vivo conditions. In addition the effects of hemofiltration on plasma low molecular weight protein concentrations, polyneuropathy, and autonomic insufficiency were also tested in a long-term (six-month) study using the membrane with the highest cutoff and most constant sieving coefficient, i.e., Highflux. Low MW proteins with a defined MW were used as marker substances. Sieving coefficients of beta 2-microglobulin, lysozyme, retinol-binding protein, alpha 1-glycoprotein, alpha 1-antitrypsin, prealbumin, albumin, and transferrin were determined during a four-hour hemofiltration (20 L ultrafiltrate). Proteins were analyzed using an immunodiffusion technique. In the long-term study, motor nerve conduction velocity, the Schellong test, and Valsalva maneuver were tested prior to and three and six months after hemofiltration therapy. Highflux, Duoflux, and FH 202 membranes were permeable to proteins with molecular weights up to 15,000 daltons, and the Highflux module had the most constant sieving coefficient during hemofiltration. In the six-month hemofiltration study with the Highflux filter, plasma beta 2-microglobulin and lysozyme decreased significantly as expected. Parameters of polyneuropathy and autonomic insufficiency were slightly improved.