Michael A. Linshaw

Renal Function Studies and Kidney Pyruvate Garboxylase in Subacute Necrotizing Encephalomyelopathy (Leigh's Syndrome)

Extract: Proximal renal tubular acidosis has been observed in two infants who had lactic acidosis associated with subacute necrotizing encephalomyelitis. Reduced renal thresholds for bicarbonate (18–19.2 mM/liter) were found in both, in conjunction with the ability to excrete normal quantities of acid. In order to raise the level of serum bicarbonate, increasing rates of infusion of solutions containing bicarbonate were required, because of a progressive increase in serum lactate from 18 to 54 mg/dl. The infusion of sodium bicarbonate expanded the extracellular space, as measured by an increase in chloride space of 12.9%. Volume expansion was associated with a progressive fall in bicarbonate reabsorption from a maximum of 1.91 to 1.02 mM/100 ml glomerular filtration rate. In addition, the tubular reabsorption of phosphate fell from 80 to 60%, urate clearance increased from 8.7 to 20 ml/min/1.73 m2, lactate clearance increased from 0.23 to 22.9 ml/min/1.73 m2, and chloride excretion increased from 0.7 to 3.14 μEq/min/1.73 m2. At autopsy, reduced activity of renal pyruvate carboxylase was demonstrated for the first time in this disease.Speculation: As a reflection of impaired lactate metabolism in subacute necrotizing encephalomyelitis (SNE), generation of ATP may be reduced in the renal cortex. This reduced supply of energy might be expected to impair reabsorption of normal quantities of filtered bicarbonate; proximal renal tubular acidosis may be the result. The fact that other evidence of proximal tubular dysfunction was not observed in the normohydrated state further suggests that failure to reabsorb filtered sodium bicarbonate may be the initial abnormality observed when the supply of energy diminishes in the renal cortex.The changes in the chloride space observed during bicarbonate infusions may provide data useful in the interpretation of changes in the renal threshold both for bicarbonate and for other solutes.Finally, it appears that subacute necrotizing encephalomyelitis may include a spectrum of biochemical abnormalities, and that only certain forms may be associated with renal tubular acidosis.

Low-renin essential hypertension—another form of childhood hypertension

Systematic exclusion of all previously described causes of hypertension in children established idiopathic essential hypertension associated with suppressed plasma renin activity as an apparently distinct entity here reported for the first time in a child. Additional features of this condition include normal rates of excretion of aldosterone, normal levels of plasma aldosterone which were not suppressed in response to mineralocorticoid administration, and an abnormally low salivary sodium-potassium ratio.

RENAL URIC ACID CLEARANCE AND EXCRETION DURING CHILDHOOD

Quantitation of uric acid (UA) excretion and clearance (CUA) are essential when evaluating patients with abnormal serum UA or UA crystalluria. Normal values for 24 hour urinary UA excretion and CUA during childhood, however, have not been reported. We measured total UA excretion, CUA and serum UA in 52 healthy children ages 2-14 years in whom creatinine clearance (CCr) was normal and urine Na > 20 mEq/l. We found a linear increase in total UA excretion and serum UA and a linear decrease in CUA/l. 73 m2 and UA excretion mg per kg body weight with increasing age. Denoting any of these variables as y and age in years as x and correlation coefficient between x and y as r, we found:95% confidence belts were established for each variable. Although total UA excretion increases with age, mean UA excretion per kg is greater in younger children and falls to upper adult norms (10 mg/kg) by age 10. Mean CUA/1.73 m2 is higher than adult norms (8-12 ml/min/1.73 m2) until age 7. Although filtered urate increases (serum UA increases, CCr/1.73 m2 is constant), CUA/1.73 m2 decreases with age. We conclude that tubular changes, either decreasing secretion or increasing reabsorption of UA, occur during childhood.

INFANTILE PSYCHOGENIC WATER DRINKING

Psychogenic water drinking has been reported only in older children and adults. We shall report successful management of three young children with psychogenic water drinking. One infant, 2½ mo. old was extremely irritable unless the oral fluid intake ranged from 1200-2100 ml/day. Urine Osm. was 42 mOsm/L and serum Osm. was 272 mOsm/L. Urine output was 1705 ml/day. Serum Na was 132 mEq/L;serum K 5.2 mEq/L;BUN 8 mg%;serum Ca 10.5 mg% and 24 hr. Ca excretion less than 3 mg/kg/24 hr. During the water loading portion of a modified Carter Robbins Test, CH2O was +10.9 ml/min/1.73m2. CH2O fell to -0.37 ml/min/1.73m2 when 3% NaCl was infused. A 6 mo. old and a 2½ yr. old had polydipsia and polyuria without dehydration and were able, after overnight water deprivation,to concentrate their urines. An abnormal maternal child relationship in two patients, and a prescribed fluid diet in the third had led to excessive water ingestion through inappropriate maternal responses. Appropriate psychological advice coupled with restriction of fluid to estimated insensible water loss plus 25-35% of expected normal urine output resulted in a “cure” in all patients within 6 weeks.In summary: Psychogenic water drinking in the very young appears to be a real entity and responds to parental counseling along with carefully monitored water restriction.Supported in part by NIH grant RR-75, RR-5624.

Potential danger of chlorpropamide therahy: Impaired excretion of a water load

A modified Carter Robbins Test was used to diagnose central diabetes insipidus (DI) in 3 patients. After 2–3 months of oral chlorpropamide 250–500 mg/day, the test was repeated. In 2 patients CH2O remained negative even during a water load of 20 cc/kg and 2½% saline load of 10 cc/kg/45 min. There was no further drop of CH2O following 0.1 units aqueous pitressin intravenously. These and one other patient with DI were then subjected to a continuous water loading test initiated by giving 25 cc/kg of water while on chlorpropamide in a dose sufficient to cause antidiuresis without hypoglycemia. Water excretion was impaired in all patients. Serum Na fell at least 10 mEq/L in each patient. Serum osmolality fell 25 mosm/kg in 2 patients and fell 20 mosm/kg and 15 mosm/kg in the other 2 patients. All patients gained weight. Chloride spaces increased from 3% to 5% after the water load. CH2O remained negative throughout the entire test in 2 patients. A third patient developed a CH2O of +0.9 cc/min/1.73 m2. This maximum CH2O occurred 6½ hours after the water load. A fourth patient developed a CH2O of +25 cc/min/1.73 m2. This maximum CH2O occurred 2 hours after the water load, subsequently fell to .6 cc/min/1.73 m2 and never again exceeded +2.1 cc/min. Since published evidence indicates that chlorpropamide acts by potentiating ADH, our data suggests that the subthreshold circulating ADH presumed to be present in our patients is not further suppressed by water loading. Therefore, a potential danger exists for anyone taking chlorpropamide who either requires intravenous therapy, or who may drink a large amount of fluid.