Renal metabolic response to acid-base changes. II. The early effects of metabolic acidosis on renal metabolism in the rat.

The early renal metabolic response was studied in rats made acidotic by oral feeding of ammonium chloride. 2 hr after feeding of ammonium chloride there was already significant acidosis. Urinary ammonia also increased after ammonium chloride ingestion and at 1(1/2) hr was significantly elevated. In vitro gluconeogenesis by renal cortical slices was increased at 2 hr and thereafter increased steadily. Ammonia production by the same slices was also increased at 2 hr, but thereafter fell and at 6 hr had decreased to levels which, although higher than those of the control, were lower than those obtained from the rats acidotic for only 2 hr. There was no correlation between in vitro gluconeogenesis and ammonia production by kidney slices from rats during the first 6 hr of acidosis, but after 48 hr of ammonium chloride feeding, these two processes were significantly correlated. The early increase in renal gluconeogenesis was demonstrable with both glutamine and succinate as substrates. The activity of the enzyme phosphoenolpyruvate carboxykinase was increased after 4-6 hr of acidosis. During this time there was a decrease in renal RNA synthesis as shown by decreased uptake of orotic acid-(5)H into RNA. Metabolic intermediates were also measured in quick-frozen kidneys at varying times after induction of acidosis. There was an immediate rise in aspartate and a fall in alpha-ketoglutarate and malate levels. There was never any difference in pyruvate or lactate levels or lactate:pyruvate ratios between control and acidotic rats. Phosphoenolpyruvate rose significantly after 6 hr of acidosis. All the data indicate that increased gluconeogenesis is an early response to metabolic acidosis and will facilitate ammonia production by utilization of glutamate which inhibits the glutaminase I enzyme. The pattern of change in metabolic intermediates can also be interpreted as showing that there is not only enhanced gluconeogenesis, but also that there may be significant increase of activity of glutaminase II as part of the very early response to metabolic acidosis.

Regulation of renal cortex ammoniagenesis. I. Stimulation of renal cortex ammoniagenesis in vitro by plasma isolated from acutely acidotic rats.

We studied the acute renal metabolic response in rats made acidotic by a single oral dose of ammonium chloride. Cortical slices from acutely (2-h) acidotic rats utilized more glutamine and produced more ammonia and glucose from glutamine than slices from normal animals. When cortical slices from normal rats were pretreated in vitro with plasma isolated from acutely acidotic rats, they achieved similar increases in glutamine utilization, ammonia formation, and gluconeogenesis from glutamine. We did not observe such stimulation in normal cortical slices pretreated in a low pH-low bicarbonate medium. Our data show that a nondialysable factor is present in plasma from acutely acidotic rats that may be responsible for the early increase in the urinary ammonia observed in such animals.

Renal metabolic response to acid base changes. I. Enzymatic control of ammoniagenesis in the rat.

Experiments were done on rats to investigate the nature of the renal response to metabolic acidosis and the changes in enzyme activity associated with increased ammoniagenesis. When metabolic acidosis was induced with oral feeding of ammonium chloride for 48 hr, there was an increase of activity of the enzyme phosphoenolpyruvate carboxykinase (PEPCK) in whole kidneys as well as in the kidney cortex. There was no change in PEPCK in liver, and glucose-6-phosphatase showed no change in kidney or liver in response to metabolic acidosis. The increase in PEPCK activity in kidney cortex varied with the degree of acidosis and there was a close correlation between cortical PEPCK activity and urinary ammonia. Kidney cortex mitochondrial PEPCK did not change in response to metabolic acidosis. An increase in PEPCK occurred as early as 6 hr after NH(4)Cl feeding, before there was any increase in kidney glutaminase I activity. Rats fed sodium phosphate, or given triamcinolone intramuscularly, developed a metabolic alkalosis, but there was increased urinary ammonia and an increase in activity of renal cortical PEPCK. Triamcinolone plus ammonium chloride induced a greater increase of PEPCK activity than triamcinolone by itself; on the contrary, the rise of glucose-6-phosphatase induced by triamcinolone was not enhanced by acidosis. Glucose-6-phosphatase from control and acidotic rats had identical kinetic characteristics. The results indicate that increased PEPCK activity is constantly related to increases of urinary ammonia. It is proposed that the increase of PEPCK activity is the key event in the ammoniagenesis and gluconeogenesis which follow on metabolic acidosis.

The effect of steroids and ammonium chloride acidosis on phosphoenolpyruvate carboxykinase in rat kidney cortex. II. The kinetics of enzyme induction.

The kinetics of the induction of rat kidney phosphoenolpyruvate carboxykinase activity after triamcinolone and ammonium chloride administration have been investigated with a view to the further differentiation of the two processes. The half-life of kidney phosphoenolpyruvate carboxykinase activity, as measured from the decay curve after a single doses of triamcinolone, is approximately 1.4 hr. This compares with a half-life for the enzyme from acidotic kidney of approximately 3.4 hr. Analysis of the data indicates that the induction of phosphoenolpyruvate carboxykinase activity by triamcinolone may be attributed to an increase in de novo protein synthesis. Induction by acidosis is qualitatively distinct and is partly attributed to a reduction in the rate of decay of phosphoenolpyruvate carboxykinase activity. The activities of the gluconeogenic enzymes glucose-6-phosphatase, fructose-1,6-diphosphatase, and phosphoenolpyruvate carboxykinase in both liver and kidney have been measured in animals separately treated with triamcinolone and ammonium chloride. Triamcinolone significantly increases the activities of liver phosphoenolpyruvate carboxykinase, kidney glucose-6-phosphatase, and kidney phosphoenolpyruvate carboxykinase only; ammonium chloride stimulates a 200% increase in kidney phosphoenolpyruvate carboxykinase, but has no effect on the other enzymes. The induction processes whereby triamcinolone increases phosphoenolpyruvate carboxykinase activities in liver and kidney differ quantitatively.

Ammonia production by the small intestine of the rat.

1. Slices of duodenum and jejunum produce ammonia from glutamine in vitro. 2. Ammoniagenesis does not increase in response to acidosis or potassium deficiency, two conditions known to cause enhanced ammoniagenesis in the kidney. 3. Gut contains glutaminase 1 as well as gamma-glutamyl transpeptidase. 4. These enzymes do not show any increase during starvation.

Trends in infant mortality inequalities in the Americas: 1955-1995.

STUDY OBJECTIVE: s: To describe overall and income related trends in infant mortality inequalities in the Region of the Americas from 1955 to 1995. DESIGN: Infant mortality rates (IMRs) were computed and their trends assessed by ordinary least squares. Overall trends in IMR inequalities among countries were analysed by comparing 10 year period IMRs, Gini coefficients, and Lorenz curves. Income related trends in IMR inequalities were assessed using 10 year period IMR ratios between the highest and the lowest quintiles of the per capita gross national product (GNP) distributions (adjusted for purchasing power). SETTING: Aggregated country data were used for all countries with over 200 thousand inhabitants (33 geopolitical units). The 10 year period midpoint IMR estimates used for the 1955-1995 time series were those published by the United Nations in 1997. MAIN RESULTS: IMRs decreased from 90.34 to 31.31 per 1000 live births between 1955 and 1995 at an average of 15.3 every 10 years. In contrast, Lorenz curves and Gini coefficients were similar for the five 10 year periods. After grouping by adjusted GNP distribution, a similar decreasing trend of IMR was observed in all groups. The rate ratio between the group at the lowest quintile and that at the highest quintile ranged from 4 to 5. The analysis of variance for repeated observations showed that there is a significant reduction in the IMR (F=130.18; p<0.01), that trends did not differ significantly among groups (F=1.16; p=0.32), and that they were approximately linear (F=155.83; p<0.01). CONCLUSIONS: Despite a sizable reduction in the infant mortality, whether or not income related, levels of IMR inequality among countries have remained almost constant between 1955 and 1995 in the Region of the Americas. Further analysis and focused interventions are needed to tackle the challenges of reducing these persistent mortality inequalities.

Influence of acute metabolic acidosis on the monomer and polymer forms of renal phosphate-dependent glutaminase.

Phosphate-dependent glutaminase (PDG) was measured in kidney cortex homogenates and mitochondria from control and acutely acidotic rats. The effect of plasma from acutely acidotic rats on PDG activity in homogenates from normal rats was also studied. Acidosis or incubation in acidotic plasma enhanced enzyme activity when measured at 1.0 mM but not at 20.0 mM glutamine. This effect was not due to increased mitochondrial permeability since similar results were obtained after solubilization of the enzyme with Triton X-100. Increased enzyme activity was observed with either the Tris (monomer) form or the borate (polymer) form of the enzyme, indicating that enhanced activity is not due to polymerization but probably to a conformational change in the enzyme such that the Km for glutamine is lowered.

Membranous glomerulonephropathy with crescents.

A case is reported in which typical histological features of idiopathic membranous glomerulonephropathy co-existed with atypical glomeruli showing cellular epithelial crescents in addition to diffuse basement-membrane thickening. These features were seen in a renal biopsy specimen taken during rapidly progressive deterioration of renal function in a patient previously known to have mild ankle edema for four years.

Use by visitors of the services of the Queen Elizabeth Hospital, Barbados, W.I.

This paper analyses data for 1990 culled from the medical records of the Queen Elizabeth Hospital, Barbados and examines the use of inpatient and emergency services by visitors to Barbados. The 473 visitors admitted represented 2.1% of all admissions. The records of 425 contained information on country of origin: 145 were from non-Caribbean and 280 from Caribbean countries. The distribution by country of non-Caribbean visitors was the same as that of regular tourist arrivals--the majority came from the USA. Canada and the UK. Caribbean visitors represented 14.4% of the tourists, but accounted for 65.9% of visitor admissions. Non-Caribbean visitors were 85.6% of tourists, but 34.1% of admissions. Young patients predominated among Caribbean, and older patients among non-Caribbean. Accidents, cardiovascular disease, alcohol-related illnesses and near drowning were commoner in the non-Caribbean visitors, while cancer and obstetrical/gynaecological problems were commoner in Caribbean visitors. Seven per cent of visitor admissions went to the Intensive Care Unit as against 0.15% of other patients. The average hospital stay of visitors was 11.7 days compared with 7.0 days for Barbadians. There were 898 visitors treated in the Accident and Emergency Department and the commonest problems were lacerations, abrasions and infections. The UK provided most of these patients. These data show that there is appreciable visitor use of the public health services. Non-Caribbean visitors use them because they fall ill on holiday, but many Caribbean visitors may come specifically for health care. The cost to the Barbadian health service is not insignificant: at the 1990 estimated bed-day cost of Bds$250, it represents a cost of Bds$1.1 million per annum to the Government for inpatient services alone, or 2% of total hospital costs.

Malnutrition, kidney size and composition.

Kidneys from 42 infants were analysed for protein, fat, water, DNA and RNA. No significant differences in composition could be found between groups of children with different degrees of weight deficit. However, in a larger series of 200, it was shown that increasing degrees of weight deficit were associated with a reduction in kidney size. In the older children with the greatest degree of weight deficit, the kidney formed a significantly higher percentage of the body weight. The general conclusion is that in the most severely malnourished children kidneys are smaller than normal.