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The amino acid-induced alteration in renal hemodynamics is glucagon independent. An oral protein load or i.v. administration of an amino acid solution results in an increase in glomerular filtration rate and renal plasma flow in both humans and animals. The change in renal hemodynamics has been attributed to the simultaneous induced rise in glucagon. Whether glucagon is necessary for the change in renal hemodynamics after an amino acid infusion was investigated. Two groups of dogs were used, and the experimental protocol was divided into four different periods (P1 through P4). Group I animals received an amino acid solution, and group II dogs received an equiosmolar solution of mannitol. In P1, the animals in both groups were hydrated with normal saline, whereas, in P2, the pancreatic clamp technique was used to fix the plasma glucagon levels. P2 served as a basal period in which measurements of glomerular filtration rate, renal plasma flow, and plasma glucagon were obtained. IN P3, group I animals received amino acid solution, and group II received mannitol and served as controls. In this period, an increase of 32 and 27% in glomerular filtration rate and renal plasma flow, respectively, in group I dogs was observed, whereas there were no significant changes in these parameters in group II. During this period, plasma glucagon remained still at basal level in both groups. In P4, an infusion of glucagon at a rate of 5 ng/kg/min was added to both groups. This maneuver resulted in a fourfold increase in plasma glucagon levels in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration of recombinant human growth hormone stimulates protein synthesis, decreases urea generation, and improves nitrogen balance in individuals with normal renal function. However, little information is available concerning the effects of growth hormone in patients with renal disease. This pilot study evaluated urea kinetics and clinical/metabolic responses to short-term growth hormone administration in five clinically stable adult patients requiring maintenance hemodialysis for end-stage renal failure. The dialysis prescription, medications, and oral calorie and protein intake of each patient remained constant during an initial control week and a subsequent 2-wk growth hormone treatment period. During treatment, growth hormone (5 or 10 mg) was administered s.c. immediately after each dialysis session. Protein and calorie intake, vital signs, body weight, and other clinical parameters remained stable throughout the 3-wk study. BUN values fell significantly (approximately 20 to 25%) during growth hormone administration compared with control week values. Similarly, urea kinetic modeling demonstrated a significant reduction in urea generation and the protein catabolic rate during each week of growth hormone treatment. Plasma insulin-like growth factor I levels rose significantly, and serum phosphorus and intact parathyroid hormone levels fell significantly during growth hormone administration. Serum glucose and other blood values remained stable. This preliminary study suggests that growth hormone administration reduces urea generation and improves the efficiency of dietary protein utilization in stable adult hemodialysis patients. Growth hormone may be a useful adjunctive therapy to diminish body protein catabolism in this patient population.
Hemodialysis with new cellulosic membranes is associated with profound granulocytopenia, with a nadir 15 min after initiation, followed by a rebound leukocytosis seen 1 h after initiation and persisting up to the termination of dialysis. The rapid reversal of granulocytopenia during hemodialysis has previously been ascribed to down-regulation of granulocyte C5a receptors. In this report, a method of characterizing C5a receptors by using a novel probe consisting of C5a attached to biotin via a six-carbon spacer chain is described. Cellulose acetate electrophoresis and cation exchange HPLC demonstrated a biotin-to-C5a ratio of 1:1. Analysis of granulocyte cell surface C5a receptors were performed with the probe with a fluorescein-avidin conjugate and by using fluorescence flow cytometry. The maximum decrease in C5a receptors was measured at the 15-min sampling time, when the number of C5a receptor decreased from 189,240 +/- 24,500 predialysis to 160,740 +/- 19,380 receptors (P was not significant) at the nadir of granulocytopenia. However, during recovery from neutropenia, granulocyte cell surface C5a receptors increased to 172,140 +/- 19,380 at 30 min and 193,800 +/- 24,510 at the end of dialysis. Concentrations of C3a and C5a peaked at 15 min and declined rapidly thereafter, but both remained significantly above baseline at all times. These studies suggest that down-regulation of C5a receptors, which is seen maximally at 15 min after initiation of dialysis, does not sufficiently account for the reversal of granulocytopenia during hemodialysis.
To identify the specific in vivo renal effect of reactive oxygen species (ROS), hydrogen peroxide (H2O2) was infused directly into the left renal artery in Munich-Wistar rats. H2O2 (5 to 50 mumol over 1 h) induced a dose-dependent increase in urine protein excretion rate in infused kidneys, reaching a maximum at the dose of 35 mumol (on average, a 60-fold increase from baseline). The H2O2 (35 mumol)-induced proteinuria peaked over 1 h and completely normalized by 24 h after the infusion. Electrophoresis revealed that the urine protein is primarily of glomerular origin. Fractional clearances of graded-size neutral dextran of larger molecular radii, an index of glomerular size selectivity, were significantly and substantially elevated immediately but normalized by 24 h after the infusion. GFR and RPF rate remained unchanged throughout the entire time course examined. The H2O2-induced proteinuria was largely prevented by pretreatment with catalase (20 mg, iv) or deferoxamine (30 mg/100 g body wt, iv). Thus, iron-dependent metabolites of hydrogen peroxide appear to be involved in this proteinuria and glomerular size-selective defect. Light and electron microscopy, including determination of anionic site density at lamina rara externa of glomerular capillary wall by polyethyleneimine staining, did not reveal any appreciable abnormality throughout the study period, including at the peak of proteinuria. Thus, ROS can cause massive, reversible proteinuria by inducing a molecular size-selectivity defect of the glomerular capillary wall without apparent ultrastructural abnormalities. The results raise the possibilities: (1) that persistent proteinuria of a variety of renal diseases may reflect persistence of pathogenic ROS acting on glomeruli because the potent proteinuric effect of ROS can be transient (2) that the light and electron microscopy abnormalities in glomeruli of ROS-induced renal injuries reported thus far may have no direct causal linkage to proteinuria; and, finally, (3) ROS-induced reversible proteinuria may relate to the mechanism of clinical functional proteinuria, which involves increased oxygen and ROS metabolism, e.g., exercise-induced proteinuria.
Leukotriene B4 (LTB4) is the major 5-lipoxgenase product released during early experimental glomerulonephritis. To test its functional relevance, its actions in the normal rat kidney and its influence on renal function in the heterologous phase of mild nephrotoxic serum-induced glomerular injury were examined. Intrarenal administration of leukotriene B4 resulted in mild vasorelaxant and natriuretic responses which were shared by 12(R)-hydroxyeicosatetraenoic acid but not 12(S)-leukotriene B4 or 12(S)-hydroxyeicosatetraenoic acid, suggesting activation of a common recognition site with a requirement for 12(R) stereochemistry. The polymorphonuclear cell-specific activator, N-formyl-Met-Leu-Phe, stimulated leukotriene B4 production from isolated perfused kidneys harvested from nephrotoxic serum-treated rats to a significantly greater degree than from control animals treated with nonimmune rabbit serum. The renal production of leukotriene B4 correlated directly and strongly (r = 0.79, P less than 0.01) with renal myeloperoxidase activity, suggesting interdependence of leukotriene B4 generation and polymorphonuclear cell infiltration. In vivo, intrarenal administration of leukotriene B4 to rats with mild nephrotoxic serum-induced injury was associated with an increase in polymorphonuclear cell infiltration, reduction in renal plasma flow rate, and marked exacerbation of the fall in glomerular filtration rate, the latter correlating strongly with the number of infiltrating polymorphonuclear cells/glomerulus, whereas inhibition of 5-lipoxygenase led to preservation of glomerular filtration rate and abrogation of proteinuria. Thus, although devoid of vasoconstrictor actions in the normal kidney, increased intrarenal generation of leukotriene B4 during early nephrotoxic serum-induced glomerular injury amplifies leukocyte-dependent reductions in glomerular perfusion and filtration rates, likely due to enhancement of polymorphonuclear cell recruitment/activation.