Dextran is a bacterial polysaccharide which is being increasingly used as a plasma substitute (1-4). Dextran molecules frequently have a molecular weight of several million, and consist of long branched chains of glucose units. For clinical use these large molecules are broken down artificially to an average molecular weight of 70,000. In the body, the larger molecular aggregates are further broken down and excreted as smaller fractions having (approximate) molecular weights less than 20,000, or are slowly metabolized.Dextran has been reported to induce diuresis regularly in patients with the nephrotic syndrome (5, 6). In addition to determining the clinical value of dextran, the intravenous infusion of hyperoncotic (12 per cent) dextran in water was used as an approach to the study of the following questions: 1) Effect of increased plasma volume on glomerular filtration rate;2) The relation of plasma volume, serum albumin concentration, and glomerular filtration rate to the glomerular permeability to albumin;3) The effect of increased post-glomerular colloid osmotic pressure on tubular reabsorption of water and solutes;4) The nature of the dextran-induced diuresis. METHODNephrotic children who showed no clinical evidence of renal failure were selected (i.e., no concomitant acidosis, azotemia and anemia). The children were recumbent during the study period. Infusions were administered
A biopsy was obtained at the time of admission and subsequently from eight children with severe kwashiorkor. The biopsies were analyzed for electrolyte content and for the quantities of certain intermediates (pyruvate, lactate, citrate and alphaketoglutarate). The results in five children who recovered are compared with those from three children who died. Significant reductions occurred in intracellular potassium, phosphate, magnesium and pyruvate, but lactate and alpha-ketoglutarate were increased. When the intracellular electrolytes were related to a specific intermediary metabolite (on the premise that the ion served as an activator or inhibitor in an enzymatic sequence leading to the production or the utilization of that intermediate) the changes assumed greater significance. A more dynamic interpretation of the data was provided by comparing ion:metabolite ratios of the initial with those of the second biopsy in patients who either recovered or died. Death from kwashiorkor was associated with a marked reversal in the sodium: pyruvate ratio and the apparent inorganic and organic phosphate to pyruvate ratios within the cell. These changes are consistent with some defect in the formation of pyruvate from phosphoenolpyruvate in a potassium-, magnesium-, phosphorus-dependent system. The citrate, magnesium and "true" inorganic phosphate to alphaketoglutarate ratios also were reversed in children who died compared to those who recovered. Such changes indicate a possible inhibition in the usual citric acid cycle pathway along which alpha-ketoglutarate is metabolized. Preliminary data on concentrations of phosphoenolpyruvate, isocitrate and oxalacetate within the muscle cell and on the activities of pyruvic kinase also are presented. The data are consistent with the hypothesis that the cellular swelling (in muscle) often characteristic of kwashiorkor leads to reduction in concentration of essential intracellular ions with inhibition of intermediary energy metabolism, thus leading to death. Since intracellular ions may function as activators or inhibitors for specific enzymes, it is suggested that changing quantities of a particular ion may be referred to the quantity of metabolite forming substrate or product of the specific enzymatic sequence. Altered ratios of ions to appropriate metabolites emphasize the possible significance of intracellular electrolytes in the biological system.
The water and electrolyte compositions of serial biopsies of skin and muscle obtained from children with severe chronic malnutrition have been related to balance data, obtained simultaneously in some of them, and to renal adjustments during hypotonic dehydration. The composition of diarrheal stools and specimens of urine obtained daily are given. While the number of observations is limited, severe chronic malnutrition with imbalance of electrolytes or water would seem to be characterized by the following features: Extracellular hypotonicity with expansion of the aqueous intracellular phase in muscle of non-atrophic children irrespective of reduction or expansion in volume of the extracellular phase. Increase in the ratio of intracellular to extracellular content of water often is accompanied by accumulation of sodium within the cell, quite independent of content or concentration of potassium in the cell. Either the osmotic properties of the cell or cell metabolism, or both, are altered. This progression is accelerated by intercurrent events of acute nature and is reversed during recovery. Death resulting from dehydration (or infection) superimposed upon severe malnutrition may be associated with sudden further expansion of the intracellular phase at the expense of the extracellular fluids. Content of sodium in the cell increases markedly. Balance data obtained in one such patient could not be reconciled with change in composition of the tissue. Slow renal and tissue response to malnutrition leads to marked reduction in total mass of tissue, but reconstitution of surviving tissue, presumably by utilization of substances released by catabolism of cells. The etiology of the characteristic hypotonicity of the body fluids is not known. Hypotonicity probably results from release of endogenous water from catabolism of cells, depletion of protein, recurrent loss of water and solute in diarrheal stools, and an intake of water relatively in excess of solute. Overhydration of the intracellular phase is a consequence of the extracellular hypotonicity. Excretion of a relatively hypotonic urine is interpreted as a defense of concentration of solutes in the body water, and reduction in the volume of glomerular filtrate might be interpreted as a limiting defense for sustaining the volume of body water. Redistribution of body water with very prompt contraction of the overhydrated intracellular phase and expansion of the extracellular phase of the body may be achieved by infusion of hypertonic solutions to severely dehydrated, malnourished, hypotonic infants. However, further careful examination of this phenomenon is needed to define the limitations of infusion and response before extensive use of hypertonic solutions in therapy of even the extreme cases can be advocated with safety. An hypothesis is hazarded concerning the development of the biochemical lesions of the cells and tissues in chronic malnutrition. It is suggested that despite apparently different clinical features, chronic malnutrition with respect to proteins and calories in infants may be interpreted as a continuous process of disturbance at a cytoplasmic level which gradually narrows the flexibility of renal and cellular responses. Superimposed acute catabolic events like diarrhea or infection eventually overcome the limits of renal and of cellular compensation, thus leading to irreversible intracellular biochemical derangement and death.
The present report deals with preliminary results on the study of renal function in advanced malnutrition. The glomerular filtration rate (clearance of inulin) and renal plasma flow (clearance of para-aminohippurate) were studied in 10 children with severe chronic malnutrition. Osmolar clearance were also measured in six of these children. In three, with marked hypotonicity despite acute dehydration, the effects of intravenous administration of a load of sodium chloride were studied. A significant reduction in filtration rate and renal plasma flow was encountered, which was most evident during dehydration. A decrease in osmolar clearance and the presence of "free-water" clearance in both non-dehydrated and dehydrated malnourished children suggested suspension of the usual antidiuretic mechanisms for conservation of water; however, the rise in osmolar clearance and reabsorption of osmotically free water following administration of hypertonic saline, indicated that the capacity of the renal tubules to respond to an adequate stimulus was not lost. Administration of an hypertonic solution of saline produced a marked expansion of the volume of extracellular fluid. More than half of this expanded volume resulted from redistribution of intracellular "endogenous" water. Expansion of volume limited rise of osmolality of extracellular fluid in two cases, but failed to do so in the third. A relatively large proportion of the filtered water was excreted during hypotonic dehydration. Filtration rates apparently decreased as the proportion of filtered water excreted became increased. The possibility that reduction in filtration rate constitutes a volume defense mechanism and that the apparent anomalies in renal function represent an adaptation to the cellular hypotonicity of the malnourished subject are discussed.
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