Sodium or chloride deficiency lowers muscle intracellular pH in growing rats.

Sodium deficiency and chloride deficiency are associated with a contracted extracellular (ECF) volume and impaired growth in young children and growing rats. In cell culture, lowering sodium in the medium reduces growth factor-stimulated Na+/H+ exchange activity, intracellular pH (pHi), and DNA synthesis. We studied the effect of chronic sodium deficiency and chloride deficiency upon growth, extracellular acid base status, and muscle pHi in young rats. We fed growing rats for 21 days either a control diet, or one deficient in sodium (0.005%), chloride (0.005%), or calories. Muscle pHi was measured using 31phosphorus nuclear magnetic resonance spectroscopy. Rats fed either the sodium-deficient or chloride-deficient diet developed ECF volume contraction and hyponatremia; growth in length and weight was impaired. Muscle pHi was decreased (pHi = 7.074 +/- 0.006, 7.078 +/- 0.006 vs. control 7.100 +/- 0.002; P < 0.02). In calorie-restricted rats, growth was impaired but pHi was not affected (pHi 7.103 +/- 0.008). Metabolic alkalosis developed in the chloride-deficient group; acid base status was not affected in the sodium-deficient group. Despite differences in ECF acid base status, both groups had a low muscle pHi. We speculate that the low muscle pHi was a result of the ECF volume contraction and hyponatremia; low muscle pHi may contribute to retarded cell growth.

A prospective, double-blind study of growth failure in children with chronic renal insufficiency and the effectiveness of treatment with calcitriol versus dihydrotachysterol. The Growth Failure in Children with Renal Diseases Investigators.

Because controlled trials in adults have shown accelerated deterioration of renal function in a small number of patients receiving calcitriol for renal osteodystrophy, we initiated a prospective, randomized, double-blind study of the use of calcitriol versus dihydrotachysterol in children with chronic renal insufficiency. We studied children aged 1 1/2 through 10 years, with a calculated glomerular filtration rate between 20 and 75 ml/min per 1.73 m2, and with elevated serum parathyroid hormone concentrations. Ninety-four patients completed a mean of 8.0 months of control observations and were randomly assigned to a treatment period; 82 completed the treatment period of at least 6 months while receiving a calcitriol dosage (mean +/- SD) of 17.1 +/- 5.9 ng/kg per day or a dihydrotachysterol dosage of 13.8 +/- 3.3 micrograms/kg per day. With treatment the height z scores for both calcitriol- and dihydrotachysterol-treated groups showed no differences between the two groups. In relation to cumulative dose, there was a significant decrease in glomerular filtration rate for both calcitriol and dihydrotachysterol; for calcitriol the rate of decline was significantly steeper (p = 0.0026). The treatment groups did not differ significantly with respect to the incidence of hypercalcemia (serum calcium concentration > 2.7 mmol/L (> 11 mg/dl)). We conclude that careful follow-up of renal function is mandatory during the use of either calcitriol or dihydrotachysterol because both agents were associated with significant declines in renal function. There was no significant difference between calcitriol and dihydrotachysterol in promoting linear growth or causing hypercalcemia in children with chronic renal insufficiency. Dihydrotachysterol, the less costly agent, can be used with equal efficacy.

Efficacy of once- versus thrice-weekly subcutaneous recombinant human erythropoietin in children receiving continuous cycling peritoneal dialysis.

The subcutaneous administration of recombinant human erythropoietin is effective in the treatment of anemia of end-stage renal disease. Single-dose pharmacokinetic studies suggest the possibility of less frequent dosing via the subcutaneous route. In this study, dosing once-weekly was as effective as thrice-weekly subcutaneous dosing in maintaining the corrected hematocrit in a group of children receiving continuous cycling peritoneal dialysis. This regimen was preferred by and beneficial to both patients and their parents.

Recombinant erythropoietin (Epogen) improves cardiac exercise performance in children with end-stage renal disease.

To determine the effects of anemia in children with end-stage renal disease, we studied cardiac performance before and 1 and 6 months after recombinant erythropoietin (Epogen). Children with end-stage renal disease were included if they had significant anemia [hematocrit (Hct) < 30%]. Epogen 50 U/kg was given subcutaneously or intravenously three times per week until the Hct was > or = 33%. Echocardiography, cardiac output (acetylene rebreathing), and treadmill (modified Bruce) tests were performed. Boys (9) and girls (9), 11.9 +/- 5.6 years, were given Epogen and the Hct increased (from 21.7 +/- 2.7% to 33.4 +/- 2.1%, P = 0.001). Heart rate decreased (P = 0.04) and stroke volume did not change. Blood pressure did not change. Cardiac thickness, chamber dimensions, left ventricular wall stress, velocity of circumferential fiber shortening, and indices of diastolic function were normal and did not change after Epogen. Exercise time increased (from 10.3 +/- 1.9 to 11.2 +/- 1.9 min, P = 0.01) after 1 month of Epogen. Resting oxygen consumption (VO2) decreased (from 7.8 +/- 1.8 to 6.9 +/- 1.4 ml/min per kg, P = 0.01) 1 month after Epogen and peak exercise VO2 did not change after Epogen. There were no differences in exercise tests between the 1 and 6 month measurements. Exercise tolerance improves after the short-term correction of anemia and there is no further improvement after long-term correction.

Plasma renin activity as a marker for growth failure due to sodium deficiency in young rats.

We evaluated the effect of feeding diets of varying sodium content on growth and plasma renin activity (PRA) in young rats. In the first study, four groups of rats were offered 10 g/100 g body weight per day of diets containing either 0.005%, 0.015%, 0.03%, or 0.3% sodium; weight gain per day of each rat was followed for 10-14 days and PRA was then measured. A control group was fed a sodium-replete tryptophan-deficient diet which caused protein calorie malnutrition and inhibited growth. Weight gain (g/day) among the rats on the sodium-deficient diets varied directly (r = 0.81, P < 0.001) and PRA inversely (r = -0.82, P < 0.001) with dietary sodium content. PRA varied inversely with weight gain (r = -0.84, P < 0.001). Insulin-like growth factor-1 (IGF-1), which is depressed in calorie-deficient growth failure, was depressed in all the rats on the low-sodium intakes relative to ad libitum-fed controls, but did not vary in relation to dietary sodium or weight gain within those groups. In rats fed the tryptophan-deficient diet, both IGF-1 and weight gain were severely depressed; PRA was normal. In the second study, rats in each of two groups were pair fed, the diet containing either 0.03% or 0.3% sodium matched to rats fed the 0.005% sodium diet; weight gain was followed for 28 days. Both length and weight gain were retarded; PRA again varied inversely with dietary sodium content and with weight gain.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of low-dose subcutaneous recombinant human erythropoietin in end-stage renal disease: experience with children receiving continuous cycling peritoneal dialysis.

The use of recombinant human erythropoietin (rhEPO) for the treatment of renal anemia is well accepted. However, the lowest effective dose for subcutaneous (SC) administration has not been determined. This study documents that a dose of 50 U/kg administered three times a week was effective in 10 children (age range, 13 days to 18.6 years) receiving continuous cycling peritoneal dialysis (CCPD) for a period ranging from 0.25 to 23.5 months. Their hematocrit (hct) increased at an average rate of 0.26% points per day from a baseline of 19.8% +/- 3.1% to a value of at least 30% after a mean of 7.4 +/- 2.5 weeks of treatment. When compared with other studies, this response was more rapid than what has been observed with the same dose administered intravenously (IV). This response was similar to that seen with larger IV doses. Hypertension and functional iron deficiency were the most common complications. Two patients with previously controlled hypertension developed elevation in blood pressure that was easily controlled by oral antihypertensives. Six patients required IV iron dextran to reestablish treatment response. A SC rhEPO dose less than 50 U/kg three times a week may be effective in children and should be investigated.

Different effects of chronic K+ depletion on forebrain and peripheral angiotensin II receptors in young rats.

K+ depletion stimulates the circulating renin-angiotensin system and affects the regulation of peripheral angiotensin II receptors. The effects of K+ depletion on the regulation of central angiotensin II receptors are unknown. We studied the effects of selective K+ depletion (less than 0.05% in diet for 16 days) on angiotensin II receptor number in kidneys, adrenal glands, and selected brain areas of young rats. K+ depletion caused a significant increase in plasma renin activity and significantly decreased angiotensin II receptor number in the kidney glomeruli and medulla, and in the adrenal zona glomerulosa and adrenal medulla. In the brain, the angiotensin II receptor number was unchanged in the subfornical organ and the hypothalamic paraventricular nucleus after 16 days of K+ depletion. An additional NaCl supplementation (0.02% in the drinking water) to K(+)-depleted rats produced a decrease in plasma renin activity but failed to affect subfornical organ or paraventricular angiotensin II receptor number. Our results suggest that in young animals, K+ depletion has a significant impact on the peripheral renin-angiotensin system without affecting the density of forebrain angiotensin II receptors.

Chronic sodium or chloride depletion upregulates angiotensin II receptors in the anterior pituitary lobe of young rats.

The effect of chronic (35 days) and selective sodium or chloride depletion on the regulation of angiotensin II receptors in the anterior pituitary gland of young male rats was studied by quantitative autoradiography. Both chronic sodium or chloride depletion produced significant extracellular fluid volume contraction, stimulation of the circulating renin-angiotensin system and increased the number of angiotensin II receptors in the anterior pituitary gland. Changes in angiotensin II receptors in both sodium- and chloride-depleted animals were associated with increased plasma prolactin levels. Our results suggest a participation of the pituitary renin-angiotensin system in the physiological response and/or possible adaptation to chronic sodium or chloride depletion. Extracellular fluid volume contraction and profound chronic stimulation of the circulating renin-angiotensin system may contribute to regulate anterior pituitary angiotensin II receptors and may influence prolactin release.

Experience with bilateral renal artery stenosis as a cause of hypertension in childhood.

Since 1981, eight children have been treated at this hospital for hypertension due to bilateral renal artery stenosis (RAS). Useful diagnostic studies were DTPA renal scan following pretreatment with captopril, and selective renal angiography. All patients underwent attempted surgical revascularization of the RAS and three had aortoaortic bypass of an abdominal aortic narrowing. Of the 14 kidneys that had repair of RAS, a successful outcome was obtained in 11 (80%). Three patients required unilateral nephrectomy. Five of eight patients are normotensive and off all medications, and three are normotensive on reduced medication doses.

Different effects of chronic Na+, Cl-, and K+ depletion on brain vasopressin mRNA and plasma vasopressin in young rats.

1. We studied the effects of selective chronic dietary sodium, chloride, or potassium depletion in young rats on vasopressin mRNA levels in the supraoptic and paraventricular nuclei, an index of vasopressin formation, and in plasma vasopressin levels, an index of vasopressin release. 2. All diets significantly increased plasma renin activity, contracted the extracellular fluid volume, and decreased serum osmolarity. 3. In the supraoptic nucleus, vasopressin mRNA levels were significantly decreased in the low-sodium group but were not significantly affected by chloride depletion. 4. There were no significant changes in vasopressin mRNA in the paraventricular nucleus after sodium or chloride dietary depletion. 5. After 2 weeks of potassium depletion, vasopressin mRNA levels were decreased in the supraoptic nucleus. When potassium depletion was prolonged for 3 weeks, vasopressin mRNA levels increased in both supraoptic and paraventricular nuclei. 6. Plasma vasopressin levels were high in animals subjected to dietary chloride depletion or to 3 weeks of potassium depletion. Dietary sodium depletion or 2 weeks of dietary potassium depletion did not significantly affect plasma vasopressin. 7. Our results show that chronic sodium, chloride, or potassium depletion differentially affect brain vasopressin mRNA and vasopressin release in young rats. 8. The effect of these diets may be mediated through changes in the extracellular fluid volume, serum osmolarity, and/or renin angiotensin system.

Severe hyperlipidemia due to multiple factors in a child with nephrotic syndrome.

An unusual case of severe hypercholesterolemia and hypertriglyceridemia is described in a child with nephrotic syndrome. The severe hyperlipidemia in this patient was most likely induced by multiple interacting factors which included the metabolic abnormalities of nephrotic syndrome, steroid therapy, the underlying genetic predisposition of ApoE-2 homozygosity as well as diet and diuretic therapy. The result of these factors was an extremely severe type III hyperlipoproteinemia. The pathogenesis of hyperlipidemia in this setting is discussed.

Different effects of sodium or chloride depletion on angiotensin II receptors in rats.

We studied the effects of selective chronic sodium or chloride depletion (0.005% in diet) on central and peripheral angiotensin II receptors in young rats. Chloride depletion produced the most significant increase in plasma renin activity and extracellular fluid volume contraction. In the brain, subfornical organ angiotensin II receptor concentration was decreased by sodium depletion and increased by chloride depletion. There were no significant changes in angiotensin II binding in the paraventricular nucleus. When sodium-depleted rats were water deprived for 3 days, subfornical organ angiotensin II receptor concentration increased, showing that normal sodium intake was not essential for increased numbers of angiotensin II receptors during dehydration. In the adrenal gland, chloride depletion decreased angiotensin II receptors in the medulla and zona glomerulosa. Conversely, sodium depletion increased angiotensin II receptors in the zona glomerulosa. In the kidney glomeruli and medulla, angiotensin II receptors were decreased by either sodium or chloride depletion. These results suggest different roles for sodium and chloride in the regulation of the peripheral and central renin-angiotensin system in young rats.

Restoration of kidney function after prolonged renal artery occlusion.

An 11-month-old child developed renal artery occlusion (RAO) and anuric renal failure following an unsuccessful transluminal renal artery angioplasty of a solitary kidney. Despite the prolonged period of anuria, kidney viability was suspected based upon preservation of kidney length and the absence of glomerulosclerosis. At 19 months of age, revascularization of the kidney was performed. During the 7 months following revascularization, renal function gradually improved so that dialysis was no longer necessary. This improvement occurred in spite of significant tubular atrophy. Kidney viability may have been preserved, despite prolonged ischemia, as a result of the decreased renal oxygen consumption that existed during subfiltration glomerular perfusion pressures. The low normal blood erythropoietin level may have reflected the lack of renal hypoxia. The ability of the kidney to adapt to chronic ischemia underscores the importance of considering vascular reconstruction in all patients with RAO despite a long period of non-function.

Down-regulation of angiotensin II receptors in subfornical organ of young male rats by chronic dietary sodium depletion.

The effect of a 4-week period of selective dietary sodium depletion on the regulation of peripheral and central angiotensin II receptors was studied in young rats, by quantitative autoradiography. Moderate sodium depletion (0.05% sodium in diet) significantly impaired growth rate and stimulated the renin-angiotensin system, but did not result in significant changes in peripheral or central angiotensin II receptors. In young rats, the impairment of the growth rate and the stimulation of the peripheral renin-angiotensin system were more notable after profound sodium depletion (0.005% sodium in diet). Such sodium depletion corresponded to a down-regulation of kidney angiotensin II receptors, and to an up-regulation of adrenal zona glomerulosa angiotensin II receptors. These effects are similar to those reported in adult rats. In the brain, profound sodium depletion down-regulated angiotensin II receptors in the subfornical organ. There were no changes in angiotensin II receptors in another brain structure, the paraventricular nucleus. Our results indicate a participation of selective central angiotensin II receptors in the regulation of sodium metabolism and suggest that factors other than circulating angiotensin II levels might contribute to regulate the number of angiotensin II receptors in the subfornical organ.

Descriptions of the participating centers and patient population in the Growth Failure in Children with Renal Diseases Study.

The Growth Failure in Children With Renal Diseases Study, a double-blind, multicenter clinical trial with 108 children entered into the control period over 4.3 years of patient enrollment (December 1984 to April 1989), is being extended for 3 years (December 1988 to December 1991) to provide the time needed to accrue additional patients, aged between 1 1/2 and 10 years, with glomerular filtration rates of 20 to 75 ml/min/1.73 m2. The study design of randomization to two treatment arms (1,25-dihydroxyvitamin D vs dihydrotachysterol) requires a total of 108 patients with a minimum of 6 months of treatment to test the long-term effectiveness and safety of 1,25-dihydroxyvitamin D, an essential part of the therapeutic regimen for children with chronic renal insufficiency. The frequent longitudinal assessments of nutrition and growth in children with chronic renal insufficiency can better define the natural history of renal disease and its influence on growth. Similar data in the treatment period will define the impact of treatment with 1,25-dihydroxyvitamin D3 versus dihydrotachysterol on this natural history. Linear growth must be observed long enough (6 to 12 months minimum) to permit valid quantitation and comparison of the two vitamin D treatment arms, the multiple confounding variables that affect growth (e.g., steroid therapy, diabetes mellitus, prior vitamin D treatment) must be rigorously excluded or controlled, and the assignment of patients to the two groups must be random. These controls--sufficient study duration, sufficient patient numbers, and randomization--should eliminate extraneous sources of variation, including seasonal periodicity. This carefully developed, double-blind clinical trial with multiple participating centers and an effective organizational structure is coming close to achieving the goals of the study. An explosion of data regarding the natural history of chronic renal insufficiency and its treatment with vitamin D metabolites will be forthcoming at the conclusion of the study.

Intravenous immunoglobulin in minimal change nephrotic syndrome: a crossover trial.

To determine whether intravenous immunoglobulin (IVGG) would be an efficacious adjunct in the treatment of childhood minimal change nephrotic syndrome (MCNS), we enrolled ten patients with frequently relapsing or steroid-dependent MCNS in a double-blind crossover clinical trial. At the time of relapse of the nephrotic syndrome, patients were assigned to treatment with a single outpatient infusion of IVGG (800 mg/kg) or intravenous albumin as a control. The relapse was treated concurrently with standard doses of oral prednisone. At the time of the next relapse, patients who had first received IVGG were treated with albumin, and vice versa. There were no significant differences in the length of remission between the IVGG and albumin treatments. The study had a power of 0.72 to detect a true difference of 45 days between the two therapies. We conclude that in the dose of drug used in this trial, administered at the time of relapse in conjunction with prednisone therapy to children with frequently relapsing or steroid-dependent MCNS, IVGG does not lead to a clinically important extension of the period of remission.

Elective subtotal splenectomy. Indications and results in 33 patients.

Elective subtotal splenectomy was performed in 33 patients (30 children and 3 adults) between 1981 and 1989. Indications for the procedure were (1) prevention of azathioprine-induced neutropenia (n = 20); (2) Type I Gaucher disease (n = 9); and (3) cholesteryl ester storage disease, chronic myelogenous leukemia, thalassemia major, and splenic cyst in one patient each. There were no operative deaths, no reoperations for bleeding, and 30 of 33 (91%) patients had a functioning splenic remnant documented by a postoperative radionuclide spleen scan. One patient developed neutropenia without evidence of viral infection that required temporary cessation of azathioprine and the patient with thalassemia major had only transient improvement in transfusion requirements. All other patients (94%) had control of the underlying condition for which the operation was performed. We conclude that subtotal splenectomy is a safe, effective therapy for a variety of nontraumatic conditions.

Renovascular hypertension in children: current concepts in evaluation and treatment.

Since 1981, we have evaluated and treated 22 children with renovascular hypertension (RVH). Seventeen patients had stenosis of their native renal arteries, and five had stenosis of the artery in a transplanted kidney. RVH was caused by fibromuscular dysplasia in 13 patients, by trauma in 2 patients, and by arteritis in 2 patients. Among the patients who had transplanted kidneys, three had technical causes for stenosis and two had stenosis due to rejection. The disease was unilateral in 10 patients, bilateral in 5, and present in a solitary kidney in 7, including the five renal transplants. Diagnostic studies that strongly suggested the presence of renovascular disease were an initial diastolic blood pressure greater than 100 mm Hg, an elevated peripheral vein renin activity level, and an abnormal renal scan if the patient's hypertension was being controlled with an angiotensin-converting enzyme inhibitor (ACEI). Only the renal arteriogram was 100% accurate in confirming the presence of RVH. Percutaneous angiographic correction was attempted in 13 patients and resulted in lasting improvement of the hypertension in five (38%). Surgical revascularization was attempted in 17 children, including the 8 with failed angioplasty, with improvement or cure of the hypertension in 15 patients (88%). Combining percutaneous transluminal angioplasty (PTA) and surgical results gave 20 of 22 patients (91%) with cure or improvement of their hypertension. Four of 27 affected kidneys (15%) could not be revascularized and were removed. We conclude from this series of patients that despite improvements in noninvasive studies, renal arteriogram remains the only study that is 100% accurate in evaluating children for RVH.(ABSTRACT TRUNCATED AT 250 WORDS)