Effect of protein diets on the renal function of baboons (Papio hamadryas) with remnant kidneys: a 5-year follow-up.

To assess the progression of renal disease and the effects of protein intake in a species phylogenically close to humans, 14 adolescent baboons (Papio hamadryas) were subjected to infarction of one third of the left kidney and, 2 months later, to right nephrectomy. They were then randomized to a synthetic protein diet containing either 8% or 25% casein. Hemodynamic and metabolic measurements were obtained in awake animals every 4 months. Modest proteinuria developed immediately after left kidney infarction, and hypertension after right nephrectomy. Proteinuria and hypertension, however, were similar in both groups and did not progress for the next 60 months. Inulin clearance markedly increased with implementation of the synthetic diet in baboons given 25% protein, in contrast to animals given 8% protein, averaging 46.6 +/- 4.7 mL/min versus 28.2 +/- 2.6 mL/min, respectively, after 4 months. The glomerular filtration rate (GFR) changed little immediately thereafter and, at 1 year, averaged 43.0 +/- 1.4 mL/min and 28.0 +/- 4.3 mL/min, respectively. During the next 4 years, however, inulin clearance steadily decreased in baboons fed 25% protein. The inverse correlation between inulin clearance and time of follow-up was y = 48.5 - 0.36x (r = -0.879, P < 0.001) in baboons fed 25% protein and y = 29.0 - 0.11x (r = -0.625, P < 0.02) in baboons fed 8% protein. Nevertheless, after 5 years, the mean GFR was still significantly greater in animals given the 25% protein diet than in baboons fed 8% protein, averaging 29.1 +/- 0.6 mL/min and 24.1 +/- 1.0 mL/min, respectively (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Renal function of baboons (Papio hamadryas) with a remnant kidney, and impact of different protein diets.

To assess progression of renal disease and the effects of protein intake in a species phylogenically close to man, 10 young adult baboons (Papio hamadryas) were subjected to 20 to 30% infarction of the left kidney and, two months later, to right nephrectomy. They were then randomized to a synthetic diet containing either 8% or 25% protein. Hemodynamic and metabolic measurements were obtained in awake animals every four months. Baseline mean blood pressure, inulin clearance, protein and urea nitrogen excretion in intact animals on 15% protein averaged 75.5 +/- 3.5 (SE) mm Hg, 42.9 +/- 2.7 ml/min, 52 +/- 4.3 mg/24 hr, and 3.8 +/- 0.4 g/24 hr, respectively. At 12 months, values in the same baboons with a remnant kidney on 8% versus 25% protein averaged 100.6 versus 96.7 mm Hg, 29.2 versus 54.9 ml/min (P less than 0.01), 111 versus 108 mg/24 hr, and 3.4 versus 11.0 g/24 hr (P less than 0.001), respectively. Electron microscopic examination of renal biopsies obtained eight months after nephrectomy was normal but for slightly increased mesangial matrix in three animals. Thus, blood pressure increased (P less than 0.01), proteinuria doubled (P less than 0.01) and adaptations in GFR developed within four months of renal mass reduction, without significant changes occurring between four and 12 months. The adaptations in GFR were markedly attenuated by low protein intake. Further follow-up is necessary to assess progression of renal disease and the impact of different protein diets.

Glomerular filtration rate and blood pressure monitoring in awake baboons.

Minimally invasive techniques were used to collect urine with an external catheter together with automated intermittent monitoring of arterial blood pressure in awake male baboons. Using endogenous creatinine, 24-hour creatinine clearances were measured for 2 to 3 consecutive days in four intact and in four uninephrectomized baboons. Despite large differences in urinary volume and sodium excretion, reproducibility of 24-hour creatinine clearances was within 15% in 15 of 19 studies obtained from 6 of 8 animals. Arterial blood pressure was monitored intermittently at 30 to 60 minute intervals over 24 hours with a Dinamap monitor and recorder. Mean blood pressure averaged 71 +/- 4.4 to 89 +/- 5.5 mm Hg in different animals. Blood pressure tended to be lower at night than during the day. In separate studies using 15 to 60 minute urine collection periods, inulin clearance was compared in awake and in anesthetized animals with endogenous or exogenous creatinine clearance measured simultaneously. The clearance of creatinine systematically exceeded the clearance of inulin, even in intact animals with a normal serum creatinine. The creatinine-to-inulin clearance ratio averaged 1.16 +/- 0.03 at a serum concentration of 0.7 to 0.8 mg/dl; 1.27 +/- 0.03 at a serum creatinine of 1.0 to 1.1 mg/dl and 1.56 +/- 0.04 at a serum creatinine greater than 10 mg/dl. All values exceed unity significantly (p less than 0.001). Thus, renal function, including inulin clearance, can be measured in awake baboons. Duplicate or triplicate 24-hour urine collections are needed to assess the reliability of creatinine excretion. However, creatinine clearance overestimates glomerular filtration rate, as it does in humans.

Glomerular function and morphology after renal mass reduction in dogs.

To determine whether the proteinuria, glomerular sclerosis, and decline in glomerular filtration rate (GFR) described in rodents after renal mass reduction develop in another species, 24-hour proteinuria, glomerular structure, and fasting and postfeeding GFR were examined in dogs subjected to seven-eighths reduction in renal mass. All dogs were fed a diet containing 26% protein. Six dogs with a GFR less than 10 ml/min (8% to 17% of control two-kidney GFR) were killed within 6 months after renal mass reduction. Twenty-four-hour urinary protein excretion was modestly although definitely increased (236 +/- 26 mg/24 hr, P less than 0.01). All remnant kidneys demonstrated structural changes of mesangial hyperplasia or focal glomerular sclerosis. Ten dogs with a remnant kidney and early GFRs 16% to 39% of control values were followed for 18 to 39 months. In seven dogs, GFR showed little tendency to decrease with time. In one of them, proteinuria was 106 mg/24 hr with normal-appearing glomeruli at 14 months. In three dogs, proteinuria was progressive, averaging about 1 gm/24 hr at 18 months and 2 gm/24 hr at 24 to 34 months; glomerular pathologic findings progressed from focal mesangial hyperplasia or focal glomerular sclerosis at 8 to 16 months to focal and segmental sclerosis or diffuse glomerular obsolescence at 25 to 34 months; and fasting GFR progressively declined starting at 21 to 24 months after renal mass reduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Renal effects of atrial natriuretic factor in primate.

Baboons (Papio hamadryas) were infused intravenously with a nonhypotensive dose (0.1 microgram X min-1 X kg-1) of synthetic human atriopeptin III (ANF) for 60 min. Throughout the infusion in intact animals, ANF significantly increased glomerular filtration rate (GFR) (clearance of inulin) (P less than 0.001), and, to a lesser extent, total renal plasma flow (RPF) [clearance of p-aminohippurate (PAH)] (P less than 0.02) and filtration fraction (P less than 0.02). Concomitant increases in urinary flow rate and in the excretion of osmoles, sodium, chloride, potassium, phosphorus, and calcium were highly significant (less than 0.001 for all). To minimize the hemodynamic impact of ANF on GFR, the same dose of ANF was infused into the same animals 8 wk after uninephrectomy. Base-line single-kidney GFR was then 50% increased. With ANF infusion RPF increased significantly (P less than 0.02), as in intact baboons, but ANF then had only marginally significant effects on GFR (P = 0.06) and insignificant effects on filtration fraction (P = 0.17). Nevertheless, the changes in urinary flow rate and solute excretion rates were highly significant (P less than 0.001 to less than 0.007). In both groups, all changes developed rapidly, were sustained during the infusion of ANF, and were readily reversible within 15 to 30 min of cessation of ANF infusion. The data dissociate in uninephrectomized primate the effects of ANF on water and solute excretion from those on GFR and filtration fraction. Both in intact and in uninephrectomized baboons, the changes in water and solute excretion were associated with small but significant changes in RPF.

Potassium-aldosterone response in dogs with chronic renal insufficiency.

To evaluate the potassium-aldosterone axis in chronic renal insufficiency, the plasma concentration of aldosterone was measured before and after a 50-mEq potassium challenge in dogs with intact kidneys (glomerular filtration rate 52 +/- 3.1 ml/min) and in dogs with one remnant kidney (glomerular filtration rate 16.1 +/- 2.1 ml/min). Fasting concentrations of circulating potassium and aldosterone and urinary potassium excretion rates were similar in both groups. In the 5 h following potassium chloride administration, less of the potassium load was excreted by dogs with one remnant kidney (30.2 +/- 3.3%) than by normal dogs (55.6 +/- 7.3%; p less than 0.01); serum potassium rose significantly more in dogs with chronic renal insufficiency than in normal animals. After potassium chloride, plasma aldosterone increased in both groups, but the increments in dogs with one remnant kidney were twice the increases in normal dogs (p less than 0.01). The increases in plasma aldosterone per unit increment in serum potassium, however, were similar in both groups (14.5 vs. 13.8 ng X dl-1/mEq X l-1). Thus, the hyperkalemia that follows a potassium load in dogs with chronic renal insufficiency is not due to a failure to secrete aldosterone but to a decrease in potassium excretion in the setting of decreased renal mass.

Calcemic and phosphaturic response to parathyroid hormone in normal and chronically uremic dogs.

It is well established that the calcemic response to parathyroid hormone (PTH) is blunted in chronic uremia and is corrected partially by 1,25(OH)2D treatment. Recent evidence suggests that PTH(1-34) and not PTH(1-84) may be the actual calcemic fragment. Equivalent doses of both peptides were infused into five normal dogs (GFR = 51 ml/min) and eight dogs with a remnant kidney and chronic renal insufficiency (GFR = 15 ml/min). Both the calcemic and phosphaturic responses were studied. Remnant dogs had a blunted calcemic response to bPTH(1-84). The increase in fractional phosphate excretion was similar. In contrast, the calcemic response to bPTH(1-34) was equivalent in remnant and normal dogs. Treatment of uremic dogs with 400 ng 1,25(OH)2D daily for 3 days restored the effect of bPTH(1-84) on serum calcium and increased the control value for tubular phosphate reabsorption from 28 +/- 3 micrograms/ml GFR to 37 +/- 4 micrograms/ml GFR (P less than 0.01). These results suggest that there is an impaired conversion of PTH(1-84) to PTH(1-34) in chronic renal insufficiency and that 1,25 (OH)2D may be involved in metabolism of PTH(1-84). In addition, the effect of PTH on fractional phosphate excretion is not magnified in nonparathyroidectomized uremic dogs.

Sodium homeostasis in dogs with chronic renal insufficiency.

Volume homeostasis in the fasting rate and 24-hr sodium balance are maintained in chronic renal insufficiency as a result of adaptations in the residual nephrons. This study evaluates the limitations to these adaptations and the dynamics of sodium excretion (UNaV) after an acute challenge with 100 mEq of sodium chloride in normal dogs (GFR 50 ml/min) and in dogs with one remnant kidney and moderate chronic renal insufficiency (GFR 15 ml/min). When food was administered with the sodium challenge, no or minimal changes in serum protein and hematocrit values occurred, and the natriuretic responses were small and equivalent in normal and remnant dogs. On the other hand, when the sodium challenge was given without food, the natriuretic response was large in normal dogs and markedly blunted in remnant. Within 5 hr of the sodium challenge, the various groups of normal dogs excreted 40 to 63% of the sodium load, but the remnant animals eliminated only 12 to 22% (P less than 0.001). The blunted natriuresis in remnant dogs was associated with a prolonged hemodilution of circulating proteins, indicating a longer lasting expansion of the intravascular volume. The blunted response was independent of sodium diet, of the administration route (p.o. vs. i.v.) or strength (isotonic vs. hypertonic) of the sodium load, and appears to result from an inability of the remnant kidney to rapidly excrete a sodium load. Thus, administration of sodium to dogs with chronic renal insufficiency leads to prolonged sodium retention, prolonged extracellular fluid (ECF) volume expansion, and requires a prolonged excretory cycle to restore 24-hr balance.

Renal handling of potassium in dogs with chronic renal insufficiency.

The dynamics of potassium excretion were examined in normal dogs and dogs with chronic renal insufficiency of at least 4 weeks' duration (remnant model). All animals, in balance on diets providing 15, 50, or 100 mEq of potassium and 100 mEq of sodium, were challenged with 50 mEq of potassium chloride. Immediately thereafter, hourly clearances were obtained for 5 hours. Irrespective of dietary potassium, mean fasting serum potassium and urinary potassium excretion (UKV) were similar in normal and remnant dogs with mean GFR's of 57 +/- 3 and 16 +/- 3 ml/min, respectively. After orogastric administration of 50 mEq potassium, serum potassium rose significantly more in remnant (2.2 to 2.5 mEq/liter) than in normal (0.9 to 1.2 mEq/liter) groups (P less than 0.001). Conversely, UKV increased significantly less, 70 to 96 vs. 151 to 194 micro Eq/min, respectively (P less than 0.001). In 5 hours, normal animals excreted 61 to 67% of the load, but remnant dogs only 30 to 37% (P less than 0.001). In all groups, UKV correlated directly with serum potassium concentration. But this relationship was markedly attenuated in the remnant groups (P less than 0.001) and independent of dietary potassium. In contrast, the same slope describes the relationship between UKV/GRF and serum potassium for all, normal and remnant, animals. The blunted kaliuresis occurred despite the more severe hyperkalemia in remnant than in normal dogs; it was not associated with significant changes in acid-base, diuresis, natriuresis, serum glucose, insulin, and glucagon concentrations and occurred despite prolonged hyperaldosteronism. The results demonstrate a severe limitation of the remnant kidney's ability to rapidly excrete a potassium load. Changes in serum potassium, or a consequence thereof, are important for the urinary excretion of potassium following its acute administration.

Reversal of secondary hyperparathyroidism by cimetidine in chronically uremic dogs.

Chronic cimetidine therapy has been shown to suppress circulating concentrations of immunoreactive parathyroid hormone (iPTH) in hemodialysis patients. To evaluate the long-term metabolic effects of cimetidine treatment, we studied seven chronically uremic dogs for 20 wk. The dogs were studied under metabolic conditions before, during, and after cimetidine therapy. iPTH fell progressively in the five treated dogs from 536+/-70 muleq/ml (mean+/-SE) (nl < 100 muleq/ml) before treatment to 291+/-25 muleq/ml at 12 wk (P < 0.001) and 157+/-32 muleq/ml at 20 wk (P < 0.001). The control dogs showed no consistent change in iPTH. The fall in iPTH was not associated with a change in serum ionized calcium. However, serum phosphorus decreased from 5.7+/-0.9 mg/dl to 3.4+/-0.2 mg/dl by the 20th wk (P < 0.05). By contrast, the serum concentration of 1,25-dihydroxycholecalciferol increased in all treated dogs from 33.4+/-4.3 pg/ml to 51.8+/-2.4 pg/ml during treatment (P < 0.01). Calcium balance was negative in all seven dogs before cimetidine (-347+/-84 mg/72 h) and remained so in the control dogs; it became positive in the five treated dogs after 12 wk (1,141+/-409 mg/72 h) (P < 0.05). Phosphorus balance, 24-h fractional phosphate excretion, and creatinine clearance remained unchanged. Pooled samples of serum obtained during the control and 20th wk of therapy were fractionated by gel filtration and the eluates assayed for immunoreactivity. The decrease in iPTH was associated with a decrease in all the immunoreactive species, indicating suppression of parathyroid gland secretion. These observations indicate that cimetidine suppressed circulating concentration of biologically active parathyroid hormone. A probable net decrease in the loss of phosphorus from bone to blood ensued, resulting in a fall in serum phosphorus. This may have stimulated synthesis of 1,25-dihydroxycholecalciferol and led to a positive calcium balance, thereby maintaining the serum ionized calcium concentration. The maintenance of phosphate balance, despite suppression of iPTH by cimetidine, indicates that factors other than hyperparathyroidism relate to phosphate homeostasis in chronically uremic dogs.

Leukopenia, hypoxia, and complement function with different hemodialysis membranes.

Complement activation during exposure of plasma to cuprophan has been postulated to cause leukopenia and hypoxia in hemodialysis patients. To determine if hypoxia is related to leukopenia and if complement activation leads to a depletion of functional complement components, we dialyzed four patients three times sequentially against each of four types of membranes: cuprophan, regenerated cellulose, cellulose acetate, and polyacrilonitrile. Within 20 min there was a marked leukopenia with cuprophan from 5541 +/- 376 to 1216 +/- 94 (P less than 0.001) and with regenerated cellulose from 5541 +/- 411 to 1533 +/- 203 (P less than 0.001). With cellulose acetate, the change from 5558 +/- 400 to 3783 +/- 341 (P less than 0.001) was less dramatic, and with polyacrilonitrile the fall from 5591 +/- 381 to 464 +/- 401 (P less than 0.02) was minimal. After 2 and 4 hours of dialysis, a rebound leukocytosis was seen with cuprophan, regenerated cellulose, and cellulose acetate, but not with polyacrilonitrile. Transient thrombocytopenia occurred with cuprophan and regenerated cellulose. In spite of the variable degree of leukopenia, all membranes induced a similar and significant hypoxia, which was progressive throughout dialysis, even during the rebound leukocytosis. After 4 hours, the mean PO2 ranged from 91 to 93 mm Hg with all membranes. Functional hemolytic titers of whole complement, C3, C5, and C4 were normal prior to hemodialysis and failed to decrease after 4 hours with any membrane. It is concluded that hemodialysis leukopenia is membrane-dependent and is not the cause of hypoxia. In addition, hemodialysis complement activation does not lead to functional complement depletion and is of no clinical significance.

Metabolic consequences of oral administration of 24,25-dihydroxycholecalciferol to uremic dogs.

24,25-dihydroxycholecalciferol [24,25-(OH)(2)D(3)], once considered a relatively inert metabolite of vitamin D(3), has been recently recognized as a metabolically active product in some species. In previous studies, we have shown that infusion of 24,25(OH)(2)D(3) into the thyroid artery of normal dogs results in prompt and complete suppression of parathyroid hormone (PTH) secretion. In this study, we have examined the metabolic consequences of oral administration of this metabolite in dogs with experimentally induced renal hyperparathyroidism. Dogs with comparable degrees of renal insufficiency (glomerular filtration rate, 10-15 ml/min) were treated for 3 wk with daily doses of either 2 mug of 24,25(OH)(2)D(3) or 50% ethanol, the vehicle in which the metabolite was suspended. After a 6-wk recovery period, treatments were reversed: dogs who had previously served as controls received the metabolite while dogs previously treated with metabolite received the vehicle. Administration of 24,25(OH)(2)D(3) resulted in a 40-60% decrease of immunoreactive PTH. This was associated with a small (0.1-0.2 mg/dl) but unequivocal decrease of serum ionized calcium. Calcium balance, which was slightly negative under control conditions, became slightly but definitively positive on treatment with 24,25(OH)(2)D(3). All other parameters measured, including total serum calcium, magnesium, phosphorus, creatinine, electrolytes, phosphorus excretion, and phosphorus balance, remained unchanged. The data support the hypothesis that 24,25(OH)(2)D(3) not only decreases PTH secretion but also functions as an anabolic hormone in bone under the conditions of this experiment.