Extracellular fluid restoration in dehydration: a critique of rapid versus slow.

We compared current recommendations for treatment of severe dehydration by World Health Organization physicians and by the American Academy of Pediatrics Committee on Pediatric Gastroenterology with those in general textbooks of pediatrics, written mostly by pediatric nephrologists. The former recommend rapid (1- to 2-h) and generous intravenous restoration of extracellular fluid (ECF) volume followed by oral rehydration therapy (ORT) to replace potassium, current maintenance, and diarrheal losses--the rapid rehydration regimen. Oral feedings usually are resumed in 8-24 h. General textbooks of pediatrics usually recommend giving 20 ml/kg saline "to restore circulation," followed by the deficit therapy regimen to correct serum electrolyte abnormalities and replace remaining deficits of water, sodium, chloride, and potassium over 1-2 days. Mortality for hospitalized patients with dehydration treated with rapid rehydration was <3 per 1,000; no recent results are reported for patients treated by deficit therapy. The rapid rehydration regimen improves patient well being and restores perfusion, so that oral feedings are readily tolerated and renal function corrects serum electrolyte abnormalities in 6 h. Amounts of saline given correspond to amounts given for treating various forms of shock. Deficit therapy regimens provide less ECF restoration and are slower at restoring perfusion; tolerance for oral feedings is delayed. Two hundred pediatric nephrologists were surveyed, asking how they would treat a patient with severe dehydration and a patient with 40% burns. Only 30 of 200 responded; 29 used a deficit therapy regimen, with 20-40 ml/kg ECF replacement, while a majority rapidly and generously restored ECF volume in burn shock. We recommend that fluid therapy chapters should stop teaching deficit therapy for treating severe dehydration and instead teach the rapid rehydration regimen.

The effect of isolated chloride depletion on growth and protein turnover in young rats.

The effects of feeding a chloride-deficient (CD) diet were examined in young, growing rats. All animals were fed the same sodium-replete, CD diet. The experimental group drank distilled water, while the control group (CS) drank distilled water supplemented with 37 mM sodium chloride. By day 15, the CD rats had negligible concentrations of chloride in their urine and had developed hypochloremic metabolic alkalosis. Both groups had comparable urinary sodium concentrations and creatinine clearances. Food intake (256 vs. 226 g), weight (108.8 vs. 47.0 g) and length (9.6 vs. 7.4 cm) gains were greater in the CS animals and the efficiency of weight gain was lower in the CD rats (25.2 vs. 42.6 g gained/g of food intake). After 15-18 days, blood was drawn for testing, body composition measurements were performed and epitrochlearis muscle protein synthesis and net degradation rates determined. When incubated with or without the addition of insulin (I), epitrochlearis muscle protein synthesis, measured as the incorporation of 14C-phenylalanine, was significantly lower in CD rats [(I+ 45.7 vs. 36.76) and (I-34.72 vs. 26.3) nmol phenylalanine/g wet weight per hour (both P < 0.05)]. Net protein degradation rates were not significantly different between the two groups. Estimated nitrogen balance was significantly diminished in CD compared with CS rats. Gastrocnemius muscle RNA concentrations were also lower in CD rats (1.34 vs. 1.60 mg RNA/g wet weight, P < 0.001), but gastrocnemius protein concentrations were equal.(ABSTRACT TRUNCATED AT 250 WORDS)

Familial lobular glomerulopathy.

A family with an unusual lobular glomerulopathy is described. Renal tissue from three males and one female in two successive generations was available for review. The glomerulopathy was characterized by a marked lobular accentuation with only a modest increase in mesangial cellularity. Immunofluorescence in two patients showed focal or diffuse staining with immunoglobulins G, A, M, and C3 in the mesangium and along the glomerular capillary basement membranes. Ultrastructural study showed amorphous granular subendothelial material distending capillary loops and mesangial regions. This material accounted for the pronounced lobular accentuation. The patients in this family presented with proteinuria, hematuria, and hypertension. Three of the four patients have sustained cerebral vascular accidents and two have died. This family is compared with a previously reported family that showed similar glomerular pathology.

The effect of sodium repletion on growth and protein turnover in sodium-depleted rats.

This study examines the consequences of sodium chloride supplementation to young rats previously made salt deficient by feeding them a sodium-deficient, chloride-replete diet. Salt-deficient rats received the test diet and distilled water for 10 days. As in our previous studies, rats cared for in this manner grew more slowly than rats fed the identical diet but allowed to drink 37 mM sodium chloride. On day 11, half of the salt-depleted animals received 37 mM sodium chloride in their drinking water. Sodium-deficient and supplemented rats were studied 1,2,5-6 and 11-12 days later. Urinary sodium rapidly rose from undetectable of 46 mEq/l urine within 1 day of supplementation and there was no further increase the next day, suggesting that extracellular fluid volumes were rapidly repleted. Food intake increased in the supplemented rats compared with the deficient animals but the difference in food intake equalled only 2.25 g/day for the first 2 days of supplementation. Over the last 12 days of the study, the slopes of both weight and length gains were equal in both the supplemented and the control group and significantly higher than those in the deficient rats. Over the course of the study, full catchup was not obtained in either length or weight. In addition to total weight and length gains, liver and kidney weights increased proportionately and by 5-6 days of supplementation were equivalent to the weights seen in the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Altered growth and protein turnover in rats fed sodium-deficient diets.

The effects of feeding a sodium-deficient (NaD) diet were examined in young, growing rats. All animals were fed the same diet and drank distilled water. In the control group the water contained 37 mM sodium chloride. After 2-3 wk body composition measurements were performed and epitrochlearis muscle protein synthesis and degradation rates determined. The experimental group gained only 45% of the wt and 70% of the length seen in the control group. The difference in wt gain could not be accounted for by differences in extracellular volume which averaged only 4% of body wt. Although total food intake was equivalent in both groups, urinary ammonia plus urea nitrogen excretion was higher in the experimental animals. Protein synthesis, measured as the incorporation of 14C-phenylalanine into muscle protein was significantly lower in NaD rats (56.58 versus 68.79) and (65.26 versus 83.88 nmol phenylalanine/h/g wet wt (both p less than 0.01) when incubated with or without the addition of insulin (1 mU/mL). Net protein degradation rates were unchanged. Gastrocnemius muscle RNA concentrations were also lower in NaD rats (1.09 versus 1.52 mg/g wet wt, p less than 0.001). There were no changes noted in the concentration of protein within either gastrocnemius or epitrochlearis muscles. These results suggest that in rats, the growth failure seen in sodium deficiency: 1) affects both length and wt gain; 2) is not associated with decreased nutrient intake; 3) is due to decreased rates of muscle protein synthesis without affecting net protein degradation rates; and 4) is associated with diminished muscle tissue RNA concentrations.

Lack of an acute effect of parathyroid hormone within skeletal muscle.

Secondary hyperparathyroidism is commonly present in patients with chronic renal failure. It has been suggested that elevated levels of parathyroid hormone (PTH) may be responsible for the glucose, amino acid and protein turnover abnormalities present in uremia. We utilized an in vitro muscle perfusion system to explore this possibility in more detail. We measured glucose uptake, muscle alanine and glutamine release, protein synthesis and both total and myofibrillar degradation rates, in the presence and absence of exogenous PTH and/or insulin. The addition of PTH either in the presence or absence of insulin had no effect on glucose uptake, protein synthesis or degradation or amino acid release by peripheral muscle tissue. Measurement of PTH revealed that 84% of the initial dose of immunoreactive hormone was still present at the end of the perfusion period. Our results suggest that PTH has no effect on skeletal muscle glucose or protein metabolism.

Protein synthesis and degradation in skeletal muscle of chronically uremic rats.

We used the perfused hemicorpus preparation to measure individual rates of protein synthesis and degradation. Using fed animals, perfused either with or without insulin, muscle protein synthesis and hemicorpus protein degradation rates were similar, but myofibrillar protein degradation was clearly increased in the uremic preparations. When the animals were fasted, differences in the rates of skeletal muscle protein turnover were apparent. Uremic rats lost more wt at both 24 and 48 hr of fasting when compared to either ad libitum fed or pair-fed controls who started fasting at body wts equivalent to our uremic rats. The accelerated wt loss was accompanied by lower rates of protein synthesis, higher degradation rates, and greater net protein catabolism in our uremic rats. Alterations in body lipid content were present in uremia and correlated with the rate of protein degradation in both control and uremic rats. These data demonstrated that even in the fed state, uremia is associated with subtle alterations in skeletal muscle protein turnover. When stressed, these alterations become more pronounced. Insufficient stores of body lipids, either due to inadequate nutrition or altered metabolism, may contribute to the alterations in muscle protein turnover seen in chronic renal insufficiency.

Protein metabolism in renal failure: abnormalities and possible mechanisms.

Currently, we have only fragmentary knowledge about alterations of protein metabolism in renal failure, yet several coherent strands appear to be emerging. CRF is, in part, a state of malnutrition, as evidenced by abnormalities of body composition and alterations of both plasma and intracellular amino acid patterns. Superimposed upon this baseline are abnormalities specific to renal disease, changes in the concentration of certain amino acids, and the buildup of nitrogenous wastes and potential metabolic toxins, and the interaction of these toxins with hormones or within metabolic pathways. In acute renal failure, or when intercurrent illness is added to CRF, there is an intensification of the metabolic derangements and an acceleration of the normal catabolic response. Current research is directed at improving protein anabolism by limiting total nitrogen intake, while at the same time, providing supplemental amino or keto acids to restore and maintain nutritional state. Other approaches involve the provision of alternate pathways for nitrogen disposal and by direct stimulation of nitrogen anabolism through the administration of branched-chain amino acids or their keto acid analogues. All would agree that these modifications must be performed on a background of adequate caloric intake and careful patient monitoring. Given the complex nature of the problem, careful prospective controlled studies will be necessary before any hypothesis can be accepted. It is likely that additional improvements will require both a better understanding of the underlying metabolic defects and, probably, the combined application of several of the ideas previously noted.

Current thinking in transplantation in infants and children.

Renal and liver transplantation are now recognized as therapeutic modalities for children with kidney and liver failure. This article reviews the general indications for transplantation, recipient selection, descriptions of the procedures, and the expected outcome of these two procedures in the pediatric setting.

Protein synthesis versus energy state in contracting muscles of perfused rat hindlimb.

The goal of these studies was to evaluate acute changes in protein metabolism in skeletal muscle in response to contractile activity. Rates of protein synthesis were measured by following L-[U-14C]phenylalanine incorporation into protein in muscles of the perfused rat hindlimb at rest, during 10 min of maximal isometric muscle contractions, and during 10 min of recovery. Synthesis measurements were carried out under conditions that ensured that the specific radioactivity of the tRNA-bound precursor amino acid was equal to that of extracellular phenylalanine. Protein degradation was estimated by measuring the release of Nt-methylhistidine. Rates of synthesis were markedly inhibited in response to muscle contractions in tibialis anterior, gastrocnemius, and plantaris but were unaffected in soleus. Rates of synthesis returned toward those observed in the resting condition during the recovery period. Rates of degradation were also markedly inhibited in response to muscle contractions. Decreased rates of synthesis correlated with reduced tissue contents of ATP and creatine phosphate, a reduced ATP/ADP, and an elevated tissue content of lactate. The results demonstrate that isometric contractions in muscles consisting of a high proportion of fast glycolytic fibers result in a marked depression in rates of protein synthesis that may be due to an altered energy state.

Effects of food deprivation and refeeding on total protein and actomyosin degradation.

Total protein and actomyosin degradation rates were determined in perfused rat hemicorpus preparations. By simultaneously measuring the release of two nonmetabolizable amino acids phenylalanine and N tau-methylhistidine from the hemicorpus, the respective rates of total protein and actomyosin degradation could be calculated. When rats were deprived of food for 48 h, the rate of total protein degradation increased to 148% of the fed controls. If rats were food deprived and then refed for 24 h, the degradation rate decreased to only 79% of the rate of fed controls. Measurement of N tau-methylhistidine release indicated that food deprivation led to a dramatic increase in the rate of actomyosin degradation (427% of fed), whereas refeeding decreased the actomyosin degradation rate to that of the fed controls. Calculations of the fractional degradation rates show that actomyosin breaks down at a much slower rate than the nonactomyosin proteins (1.5 vs. 20.8%/day in preparations from fed rats, and 6.2 vs. 28.2%/day in preparations from food-deprived rats). Therefore, the contribution of actomyosin breakdown to total muscle protein breakdown is small in the fed state (11%) and increased threefold after food deprivation. The addition of insulin to the perfusion medium decreased the rate of total protein degradation by 18% in preparations from food-deprived rats with no significant effect on actomyosin degradation. Thus, in vitro, insulin's major effect may be to decrease the degradation of more rapidly turning over, nonactomyosin proteins. Protein degradation, as well as protein synthesis, contributes to the adaptation of muscle to starvation and refeeding.(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin D Deficiency, hypocalcemia, and increased skeletal muscle degradation in rats.

The myopathy associated with vitamin D deficiency was examined in vitamin D-deficient and vitamin D-supplemented rats. When compared with either vitamin D-supplemented ad lib. or pair-fed rats, weight gain and muscle mass were decreased in vitamin D-deficient hypocalcemic animals. With the exception of a modest decrease in muscle creatine phosphate levels, muscle composition was unchanged by vitamin D deficiency. Muscle protein turnover rates were determined in both in vivo and in vitro studies and demonstrated that myofibrillar protein degradation was increased in vitamin D deficiency. Normal growth rates could be maintained be feeding the rats vitamin D-deficient diets containing 1.6% calcium, which maintained plasma calcium within the normal range. In addition to its role in maintaining plasma calcium, vitamin D-supplemented rats had significantly higher levels of the anabolic hormone insulin. Vitamin D supplementation may affect muscle protein turnover by preventing hypocalcemia, as well as directly stimulating insulin secretion, rather than by a direct effect within skeletal muscle.

N tau-methylhistidine release: contributions of rat skeletal muscle, GI tract, and skin.

The relative contributions of skeletal muscle, gastrointestinal tract, and skin to urinary N tau-methylhistidine (MH) excretion were estimated during in vitro studies using the rat hemicorpus preparation. After 0.5 h of perfusion, MH release into the perfusate was linear for 3 h and averaged 29.8 nmol . h-1 . 100 g hemicorpus-1. In vivo, 24-h urinary MH excretion averaged 37.3 nmol . h-1 . 100 g body wt-1. The ratio of soft tissue to skin weight is equal (3.2:1) in the whole rat and in the hemicorpus. The gastrointestinal tract released 16.0 nmol . h-1 . 100 g body wt-1 or approximately 41% of the total urinary MH excretion. Preparations perfused with or without skin showed modest differences in the rate of MH release that were not statistically significant. Skeletal muscle contains 89.8% of total body MH content, whereas gastrointestinal tract and skin contain 3.8 and 6.4%, respectively. Gastrointestinal tract actomyosin turns over rapidly with a fractional catabolic rate of 24%/day versus 1.4%/day for skeletal muscle actomyosin.

Prenatal diagnosis of Duchenne muscular dystrophy: failure of amniotic fluid and maternal serum N tau-methylhistidine analyses to detect affected fetuses.

N tau-Methylhistidine (MH) and creatinine levels were determined in amniotic fluid and maternal serum from 81 women undergoing midtrimester amniocentesis for reasons other than the diagnosis of neuromuscular disease. Samples were also examined in three pregnancies with male fetuses who were subsequently found to have Duchenne muscular dystrophy (DMD). Between 16 and 20 weeks' gestation, amniotic fluid and maternal serum MH levels averaged 3.22 and 1.94 mumoles/L, respectively. No significant differences were found between the control and affected fetuses for MH and creatinine levels or for MH/creatinine ratios from amniotic fluid or maternal serum. Determination of amniotic fluid MH level thus has no apparent value in the prenatal diagnosis of DMD.