Role of atrial natriuretic peptide in adaptation of sodium excretion with reduced renal mass.

The kidney maintains constancy of body fluid volume by regulating urinary sodium (Na) excretion. In chronic renal failure, the reduction in glomerular filtration rate (GFR) is accompanied by an increase in Na excretion per nephron if dietary Na intake is not changed. Reduction in Na intake in proportion to reduced GFR obviates this adaptive increase in tubule Na excretion. To examine the potential role of endogenous atrial natriuretic peptide (ANP) in modulating the enhanced Na excretion per nephron in chronic renal failure, we studied rats subjected to 5/6 nephrectomy or sham operation on low, normal, and high Na intakes. Urinary Na excretion increased with increasing dietary Na in all groups, and Na excretion per nephron was increased in 5/6 nephrectomized rats as compared with sham-operated rats on the higher Na intakes. Plasma ANP levels were unaffected by dietary Na manipulations in sham-operated rats, but rose progressively in 5/6 nephrectomized rats with increasing Na intake. Despite extensive nephron reduction, however, plasma ANP levels failed to rise in uremic rats on low Na diets and in this group Na excretion per nephron also failed to rise. We conclude that enhanced ANP secretion may play an important role in promoting the adaptive increase in Na excretion per nephron in chronic renal failure. Restriction of dietary Na in the setting of reduced GFR obviates the stimulation of ANP secretion as well as the adaptive increase in Na excretion rate per nephron.     

The influence of salt intake on the metabolic acidosis of chronic renal failure

The influence of dietary salt on the levels of plasma bicarbonate and on the characteristics of bicarbonate reabsorption was studied in experimental chronic renal failure. Chronic renal failure was produced in rats by sequential partial nephrectomies. The control group received a diet constant in salt content throughout the progression of renal failure; the other group (PRNa), at each stage of renal failure, received salt intake reduced in direct proportion to the fall in glomerular filtration rate (GFR). In the steady state, the quantities of urinary sodium closely approximated intake in obth groups of animals. The adaptive increased natriuresis per nephron exhibited by the control animals was prevented in the PRNa animals. The PRNa group had (a) higher plasma bicarbonate levels, (b) increased bicarbonate thresholds, and (c) increased maximal tubular reabsorptive capacity for bicarbonate. As renal failure progresses, dietary salt can become a determining factor of the levels at which plasma bicarbonate is maintained. Proportional reduction of dietary salt results in bicarbonate conservation in rats with experimental progressive renal failure.     

On the pathogenesis of hyperparathyroidism in chronic experimental renal insufficiency in the dog

Healthy adult dogs were subjected to stepwise reduction of nephron population so as to create the transition from normal renal function to advanced renal insufficiency. Studies were performed at each level of renal function. Glomerular filtration rate (GFR), renal phosphate clearance, and serum radioimmunoassayable parathyroid hormone (PTH) levels were measured. Two groups of animals were studied. In one, phosphorous intake was maintained at 1200 mg/day. As GFR declined, fractional phosphate excretion rose reciprocally, and PTH levels increased over 20-fold. In the second group, phosphorous intake was maintained at less than 100 mg/day. As GFR fell, fractional phosphate excretion changed little, and no increment in PTH levels occurred. The data suggest that the control system regulating phosphate excretion contributes importantly to the pathogenesis of secondary hyperparathyroidism in advancing renal insufficiency.     

On the adaptation in potassium excretion associated with nephron reduction in the dog

An effort to examine certain aspects of the adaptation in potassium excretion associated with nephron reduction was made in dogs with unilateral remnant kidneys. A constant intake of potassium was maintained by tube feeding and studies were performed before and after removal of the intact control kidney. The removal of the intact kidney created the need for the remaining nephrons of the remnant kidney to increase their rate of potassium excretion markedly. Sodium intake was held constant either at a normal or a low level. Mineralocorticoid hormone activity was maintained either at a high level by the administration of 0.2 mg 9-α-fluorohydrocortisone daily or at a low level by performing bilateral adrenalectomy and administering a minimal maintenance dose of deoxycorticosterone acetate (DOCA) and cortisol. Potassium excretion per nephron increased strikingly within 18 hr of contralateral nephrectomy and by 7 days, excretion rates were 600% of control values for the remnant kidney. More potassium was excreted in the first 5 hr after administration of a test dose of potassium by the remnant kidney alone in the postnephrectomy state than by both the remnant and intact kidneys in the prenephrectomy state. 24 hr excretion of potassium by the remnant kidney postnephrectomy averaged 92% of the administered load of potassium. The adaptation in potassium excretion was independent of the concurrent rate of sodium excretion and of mineralocorticoid hormone activity and persisted during constriction of the renal artery, a stimulus which presumably decreased distal delivery of sodium. The adaptation and the continued modulation of potassium excretion could not be explained adequately by an increase in impermeant anion excretion per nephron. Finally, known changes in hydrogen ion excretion per nephron associated with nephron reduction are in a direction opposite to those which would explain the acquired kaliuresis per nephron.     

Mechanism of change in the excretion of sodium per nephron when renal mass is reduced

As the population of nephrons is reduced, sodium excretion per nephron must increase if sodium balance is to be maintained. The mechanism of this adjustment was studied in rats in which 50% and approximately 85% of renal tissue was excised. Although glomerular filtration per remaining nephron rose after uninephrectomy, it did not rise further when more renal tissue was removed, even though sodium excretion per nephron mounted. Hyperfiltration does not, therefore, account for the stepwise increase in sodium excretion per nephron with progressive renal ablation. Proximal tubular absorption, estimated by reabsorption half-time, was unchanged by renal insufficiency, indicating that "third factor" did not produce the observed changes in sodium excretion per nephron. It seems likely that the earliest adjustments in sodium excretion in renal failure take place in the distal tubules of healthy nephrons, and that they are conditioned by changes in the osmotic load per nephron.     

Control of phosphate excretion in uremic man

The present studies were performed in an effort to examine the characteristics of the control system governing phosphate excretion in uremic man. In a group of patients with glomerular filtration rates (GFR) ranging from normal to 2 ml/min, it was found that the lower the GFR the lower the fraction of filtered phosphate reabsorbed (TRP). On a fixed phosphate intake, phosphate excretion rate was the same in patients with GFRs ranging from 60 to 3 ml/min. When plasma phosphate concentrations were diminished to subnormal levels in hyperphosphatemic, hypocalcemic uremic patients, TRP values increased but did not return to normal. TRP failed to rise substantially when GFR, as well as plasma phosphate concentrations, were diminished. In patients with unilateral renal disease, TRP values were equal bilaterally, and values were substantially higher in the diseased kidneys than in patients with bilateral involvement. When plasma calcium concentrations were raised to normal for 2-3 wk in uremic patients in whom plasma phosphate concentrations had previously been lowered to subnormal levels, TRP values rose to an average value of 86%. Values remained in the normal range when phosphate concentrations were allowed to increase while normocalcemia was maintained. The data are interpreted to indicate that in advancing renal disease, the changing patterns of phosphate excretion are mediated by a control system in which parathyroid hormone serves as a major effector element. An increase in GFR per nephron, hyperphosphatemia, and intrinsic inability of the surviving nephrons to transport phosphate do not appear to be of primary importance in the progressive reduction in TRP.     

Calcium phosphate microcrystals in the renal tubular fluid accelerate chronic kidney disease progression

The Western pattern diet is rich not only in fat and calories but also in phosphate. The negative effects of excessive fat and calorie intake on health are widely known, but the potential harms of excessive phosphate intake are poorly recognized. Here, we show the mechanism by which dietary phosphate damages the kidney. When phosphate intake was excessive relative to the number of functioning nephrons, circulating levels of FGF23, a hormone that increases the excretion of phosphate per nephron, were increased to maintain phosphate homeostasis. FGF23 suppressed phosphate reabsorption in renal tubules and thus raised the phosphate concentration in the tubule fluid. Once it exceeded a threshold, microscopic particles containing calcium phosphate crystals appeared in the tubule lumen, which damaged tubule cells through binding to the TLR4 expressed on them. Persistent tubule damage induced interstitial fibrosis, reduced the number of nephrons, and further boosted FGF23 to trigger a deterioration spiral leading to progressive nephron loss. In humans, the progression of chronic kidney disease (CKD) ensued when serum FGF23 levels exceeded 53 pg/mL. The present study identified calcium phosphate particles in the renal tubular fluid as an effective therapeutic target to decelerate nephron loss during the course of aging and CKD progression.     

Atrial natriuretic peptide and adaptation of sodium urinary excretion in patients with chronic renal failure

1. In order to examine the potential role of endogenous atrial natriuretic peptide (ANP) in modulating the increased sodium excretion per nephron in chronic renal failure, we studied healthy subjects with normal renal function (group I) and patients with moderate (group II) or severe chronic renal failure (group III) before, during and after administration of an intravenous sodium load. All subjects had been on a controlled diet containing 120 mmol of sodium per day for 5 days before the study. 2. Under basal conditions, plasma ANP and fractional excretion of sodium (FENa) were highest in group III. Both parameters increased in response to the sodium load in the three groups studied (P less than 0.001). Changes with time differed from group to group (P less than 0.05), the more marked response for both parameters being observed in group III. After adjustment with respect to plasma ANP (analysis of covariance), FENa was no longer modified in response to the sodium load, whereas adjustment of FENa with respect to mean blood pressure was without consequence on the significance of its change with time. This demonstrates that plasma ANP, but not mean blood pressure, represents the main factor producing variation in FENa during and after the sodium load. 3. These results suggest an important role for plasma ANP in promoting adaptation of short-term sodium excretion in response to an acute sodium load in patients with chronic renal failure who ingest a normal sodium intake.     

On the Adaptation in Sodium Excretion in Chronic Uremia. THE EFFECTS OF “PROPORTIONAL REDUCTION” OF SODIUM INTAKE

Renal mass and glomerular filtration rate (GFR) were reduced from normal to approximately 15% of normal in two groups of dogs. One group received a constant salt intake (CSI) throughout the study. The second group was subjected to "proportional reduction" of sodium intake (PRS), a dietary regimen which involved the reduction of sodium intake in exact proportion to the decrement in GFR. In the CSI group, absolute sodium excretion rate (U(Na)V) remained essentially unchanged as GFR fell, while fractional sodium excretion (FE(Na)) increased progressively from a mean control value of 0.3% to a final value of 4.4%. In the PRS group, U(Na)V decreased with each reduction in GFR and salt intake, and FE(Na) remained constant throughout. In a second study, the fraction of serum that previously has been shown to possess natriuretic activity in studies of uremic patients was obtained from a group of uremic dogs on the CSI and from another group on the PRS regimen, and the effects of the fraction was measured on sodium excretion in rats. The serum fractions from the dogs on the CSI regimen produced a significant increase in both U(Na)V and FE(Na) in the assay rats. The same serum fraction from the dogs on the PRS regimen failed to produce a significant increase in either U(Na)V or FE(Na).The data are consistent with the view that (a) The increase in FE(Na) in chronically uremic dogs is dictated by the requirements for external sodium balance and may be prevented by prospective manipulation of salt intake: (b) a natriuretic factor, previously shown to exist in the serum of patients with chronic uremia, is also demonstrable in the serum of uremic dogs; and (c) with the present bioassay system, the factor is not detectable in the serum fraction of uremic dogs in which the requirements for an increased natriuresis per nephron have been obviated.     

Studies on the control of sodium excretion in experimental uremia

A study of the mechanisms governing the high rate of sodium excretion per nephron characteristic of patients with chronic renal disease has been made in dogs. A "remnant kidney" was produced by 85% infarction of the left kidney while the right kidney was left intact. A bladder-splitting procedure allowed simultaneous measurement of glomerular filtration rate and the rate of sodium excretion by each kidney. The animals were fed a constant known amount of sodium chloride and 0.1 mg of 9 alpha-fluorohydrocortisone twice daily throughout the study.In a group of dogs fed 3 or 5 g of salt per day, sodium excretion by the remnant kidney averaged 6.5 muEq/min while the intact kidney was present and 53.7 muEq/min when the animals became uremic after the intact kidney was removed. The increased sodium excretion per nephron by the remnant organ often occurred within 18 hr after contralateral nephrectomy and persisted despite experimentally induced acute reductions in the glomerular filtration rate to below prenephrectomy levels. A second group of animals studied in the same manner but receiving 1 g of salt per day or less failed to develop a natriuresis after contralateral nephrectomy despite high grade uremia. Thus an increased impermeable solute load per nephron was not a regulatory factor in the production of the natriuresis. The increased rate of sodium excretion per nephron in uremia resembles that after saline loading in that it may occur without an increase in glomerular filtration rate or a reduction in mineralocorticoid stimulation. It follows that an additional factor or factors must be involved in the genesis of the natriuresis.In contrast to the natriuresis that is seen in normal animals subjected to saline loading, these uremic animals were found not to have a detectable increase in extracellular fluid volume or blood volume in the presence of high fractional sodium excretion rates.Sodium excretion in response to a small salt load by the remnant organ in uremia was 30% greater than the response of both kidneys in the preuremic state despite a markedly reduced total GFR. These data are consistent with the view that the volume control mechanism becomes more responsive in uremia.     

Atrial natriuretic factor and changes in dietary sodium intake in patients with chronic renal failure

1. In order to examine the potential role of atrial natriuretic factor in modulating the increased sodium excretion per nephron in chronic renal failure, we studied 12 uraemic patients on the last day of two successive 7 day periods during which their sodium intake was 100 and 20 mmol of sodium/day, respectively. 2. There was a parallel decrease from 6.31 +/- 0.75 to 2.17 +/- 0.32% in the fractional excretion of filtered sodium and from 234.4 +/- 74.9 to 80.6 +/- 20.3 pg/ml (supine position) or 140.1 +/- 43.6 to 60.7 +/- 14.6 pg/ml (upright position) in plasma atrial natriuretic factor. Both parameters were significantly correlated during the two periods of different sodium intake (P less than 0.05). The ratio of plasma guanosine 3':5'-cyclic monophosphate to plasma creatinine changed proportionally to plasma atrial natriuretic factor. Plasma aldosterone and plasma renin activity increased during the sodium-depleted period but only plasma renin activity was significantly correlated with fractional excretion of filtered sodium. 3. The predominant role of atrial natriuretic factor compared with that of aldosterone in the renal response to varying sodium intake is suggested both by regression analysis and by the effect of 5 day's treatment with a converting enzyme inhibitor (enalapril) in six other uraemic patients on a normal (100 mmol/day) sodium intake. Such treatment, although resulting in a significant increase in plasma renin activity and a significant decrease in plasma aldosterone, at least in the supine position, did not modify the fractional excretion of sodium and plasma atrial natriuretic factor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal tubular effects of chronic phosphate depletion.

The effects of chronic phosphate depletion on renal tubular function were evaluated by micropuncture and free water clearance studies in the dog. Proximal tubular punctures demonstrated that chronic hypophosphatemia led to a reduction in ratio of tubular fluid to plasma inulin in late superficial tubular from 1.59+/-0.08 in control animals to 1.29+/-0.06 in phosphate-depleted dogs, with proportional inhibition of calcium and sodium reabsorption. The chronic decrease in proximal tubular fluid reabsorption was confirmed by the analysis of sustained water diuresis in conscious, phosphate-depleted dogs, before and after repletion of body PO4 stores, and in control animals. Urine flow rate/100 ml glomerular filtration rate (V/GFR) was significantly higher in PO4 DEPLETION THAN CONTROL (15.8+/-1.1 VS. 10.7+/-0.82). In addition, acetazolamide infusion did not increase V/GFR in phosphate-depleted dogs (15.8+/-1.1 vs. 17.16+/-0.9), supporting the conclusion that inhibition of proximal tubular fluid reabsorption was responsible for the elevated urine flow rate. PO4 repletion over 5 days reduced V/GFR to 9.2+/-0.7 despite no change in urine osmolality and no change in GFR, further suggesting a specific reversible alteration in proximal tubular reabsorption in phosphate depletion. Although hypercalciuria was a constant finding in phosphate depletion (fractional excretion of calcium of 2.04+/-0.4% vs. 0.47+/-0.13% in controls), the enhanced distal delivery of calcium was not a crucial factor; acute phosphate infusion reduced urinary calcium excretion to control values without affecting the reduced proximal tubular reabsorption in either intact or thyroparathyroidectomized phosphate-depleted dogs the change in distal nephron calcium reabsorption was independent of parathyroid hormone (PTH) levels since infusion of PTH failed to alter urinary calcium excretion. We conclude that chronic phosphate depletion leads to a reversible, sustained inhibition in proximal tubular reabsorptive fuction as well as a specific decrease in distal nephron calcium reabsorption. This latter reabsorptive defect is sensitive to phosplate infusion but not corrected by PTH.     

Effects of adrenalectomy and chronic adrenal corticosteroid replacement on potassium transport in rat kidney

Clearance experiments were carried out in pair-fed rats to examine the long-term effects of adrenalectomy and selective adrenal corticosteroid replacement in physiological amounts on renal potassium transport. To this end, clearance studies were conducted in rats that were sham operated, or adrenalectomized (ADX). ADX animals were given either vehicle, aldosterone (0.5 microgram/100 g body wt per day), dexamethasone (1.2 micrograms/100 g body wt per day), or aldosterone and dexamethasone, by osmotic minipump for 7-9 d whereupon clearance experiments were conducted. After chronic hormone treatment, during basal conditions when only Ringers solution was infused, all groups excreted similar amounts of potassium. However, in all ADX animals without mineralocorticoid replacement, the maintenance of urinary potassium excretion at control levels was associated with hyperkalemia, increased urine flow, and natriuresis; all are factors known to stimulate urinary potassium excretion. During acute potassium infusion, the increase in urinary potassium excretion was less in ADX rats than in controls. This functional deficiency in potassium excretion was partially corrected by dexamethasone and was uniformly associated with a significant increase in urine flow. Aldosterone replacement or aldosterone and dexamethasone given together chronically, sharply increased potassium excretion but did not restore excretion to control levels. Only acute aldosterone infusion (0.2 microgram/100 g body wt bolus plus 0.2 microgram/100 g body wt per hour), superimposed upon chronic aldosterone and dexamethasone treatment, fully restored potassium excretion to control levels. This aldosterone induced enhancement of potassium excretion, both chronic and acute, was not associated with hyperkalemia, and increased urine flow or natriuresis. Thus, physiological levels of both classes of adrenal corticosteroids stimulate renal potassium excretion albeit by different mechanisms. Mineralocorticoids stimulate tubular potassium excretion directly, whereas glucocorticoids augment excretion indirectly by increasing fluid and sodium delivery along the distal nephron.     

Mode of action of parathyroid hormone and cyclic adenosine 3′,5′-monophosphate on renal tubular phosphate reabsorption in the dog

To evaluate the effects of parathyroid hormone and cyclic adenosine monophosphate on proximal tubular sodium and phosphate reabsorption, micropuncture studies were performed on dogs that received a highly purified preparation of parathyroid hormone (PTH), dibutyryl cyclic 3',5'-adenosine monophosphate (cyclic AMP), 5'-AMP, and saline. PTH resulted in a 30-40% inhibition of sodium and phosphate reabsorption in the proximal tubule unassociated with a rise in either total kidney or single nephron glomerular filtration rate (GFR). The bulk of the phosphate rejected proximally was excreted in the final urine while sodium excretion rose minimally despite the marked proximal inhibition, consistent with the presence of reabsorptive sites in the distal nephron for sodium but not phosphate. The infusion of dibutyryl cyclic AMP either systemically or directly into the renal artery inhibited proximal sodium and phosphate reabsorption in the absence of changes in either total kidney or single nephron GFR, resembling the effects of PTH quantitatively and qualitatively. In contrast, another adenine nucleotide, 5'-AMP, did not inhibit the reabsorption of either sodium or phosphate. These observations support the thesis that renal effects of PTH are mediated via stimulation of renal cortical adenyl cyclase. The infusion of a moderate saline load, 25 ml/kg, also produced a similar inhibition of proximal tubular fractional sodium and phosphate reabsorption with a marked phosphaturia but only minimal natriuresis. Thus, changes in sodium and phosphate reabsorption occur in parallel in the proximal tubule when sodium reabsorption is inhibited either with volume expansion or with administration of "specific" phosphaturic agents such as PTH or cyclic AMP. These data are consistent with the thesis that phosphate reabsorption is dependent upon proximal tubular sodium reabsorption wherein the phosphaturic effect of PTH might be the result of a primary inhibition of proximal tubular sodium reabsorption mediated by adenyl cyclase stimulation.     

The acidosis of chronic renal failure

The acidosis of chronic renal failure is not due to bicarbonate wastage per se; rather, bicarbonate reabsorption per nephron is markedly enhanced. The ability to lower the urine pH is preserved. While overall ammonium production may be decreased in chronic renal failure, both ammonium production and excretion are markedly increased when expressed per remaining nephron. Titratable acid excretion in chronic renal failure is essentially maximal, owing to the effect of parathyroid hormone on phosphate excretion by the kidney. Thus, it appears that the acidosis of chronic renal failure is solely the consequence of the reduction in functional renal mass. Extrarenal buffering may contribute substantially to the maintenance of a near normal acid-base status in patients with marked reduction in glomerular filtration rate. That homeostasis is so well preserved until glomerular filtration rate falls to approximately 10 per cent of normal is remarkable; the price, however, may be considerable. Prolonged acidosis may magnify the tendency of renal failure to cause osteodystrophy. An obvious treatment for the acidosis of renal failure is exogenous alkali therapy. Most clinicians withhold alkali therapy until the bicarbonate concentration falls below 20 mEq per L. If the acidosis cannot be safely corrected with exogenous therapy, dialysis should be initiated.     

Urinary sodium excretion in patients with nephrotic syndrome, and its circadian variation

We analysed sodium excretion and its circadian variation in70 patients with nephrotic syndrome and 19 healthy controlsover 1–3 days, with a regimen of bed rest and constantsodium intake around the clock. We sampled urine and blood andtook their blood pressure every 3 h. We also scored 60 renalbiopsies for presence of interstitial fibrosis and tubular atrophy.Peripheral oedema was estimated in 37 patients. Fifty-nine patients excreted >10mmol sodium per 24 h, inequilibrium with dietary intake. In group A (n = 24), sodiumexcretion followed a normal circadian rhythm, with a daytimepeak. In group B (n = 35), 29 had reversed circadian rhythmwith a night-time peak, and 6 had no apparent rhythm. Nephroticsyndrome was more severe in group B than in A (serum albumin19.5 vs. 24.1 g/l, p<0.05; oedema 7.0 vs. 3.8 kg, p<0.01).Group B also had signs of more advanced renal disease (GFR 49vs. 99 ml/min; number of biopsies with tubulo-interstitial damage:20/28 vs. 4/23; p< 0.001). Reversed sodium rhythm was associatedwith reversed circadian rhythms for GFR, effective renal plasmaflow and urine flow, and blunting or reversal of the day-nightdifferences in blood pressure and plasma renin activity. Elevenpatients had urinary sodium excretion <1 mmol/24 h. Withrespect to severity of nephrosis, they resembled group B, butGFR and incidence of tubulointerstitial lesions were like groupA. Half of the patients with nephrotic syndrome had reversed circadianrhythm for sodium excretion. This nocturnal peak in natriuresis(and diuresis) may be due to re-entry of oedema fluid into thecirculation, with a subsequent increase in renal blood flowand GFR, and especially occurs in patients with structural tubulointerstitialdamage, where sodium reabsorption is incomplete.     

Practical management of chronic renal failure.

Initial evaluation of patients with chronic renal failure demands a careful search to exclude reversible causes such as dehydration, obstruction and nephrotoxins. Subsequently, strict management of sodium and fluid intake is necessary to avoid either dehydration or congestive heart failure. As renal failure advances, restriction of dietary protein and potassium and binding of phosphate are indicated. Referral to an end-stage renal disease center should be accomplished early, before and appearance of uremic symptoms, to facilitate a smooth transfer to the next phase of rehabilitative therapy.     

Evidence for enhanced distal tubule sodium reabsorption in chronic salt-depleted dogs.

In order to assess the renal tubular site(s) at which sodium reabsorption is enhanced in chronic sodium-depletion, seven normal dogs, six salt-depleted dogs, and three normal dogs receiving aldosterone were studied during a steady-state water diuresis under Pentothal anesthesia and during progressive hypotonic saline diuresis. For both maintenance of the water diuresis and progressive hypotonic saline diuresis 0.45% NaCl was used. During the steady state water diuresis delivery of sodium to the diluting segment of the nephron as approximated by solute-free water clearance + sodium clearance/glomerular filtration rate (CH2O + CNa/GFR) was significantly lower in salt-depleted dogs compared to normal dogs with or without aldosterone. During progressive hypotonic saline infusion fractional free water excretion (CH2O/GFR) was similar in all three groups as CH2O + CNa/GFR increased up to 12-14 ml/min-100 ml GFR. Thereafter, CH2O/GFR continued to rise in virtually a straight line in salt-depleted dogs but leveled off in normal dogs with or without aldosterone. These data demonstrate that enhanced sodium reabsorption in the diluting segment of the nephron is an important determinant of the renal sodium retention in chronic extracellular volume contraction in dogs in addition to confirming the presence of increased proximal tubule sodium reabsorption in these animals.     

Interaction of renal prostaglandins with the renin-angiotensin and renal adrenergic nervous systems in healthy subjects during dietary changes in sodium intake

In six healthy subjects the role of renal prostaglandins (PG) in modulating the actions of the renin-angiotensin and renal adrenergic nervous systems on renal function was investigated. During high dietary sodium intake (350 mmol/day) for 4 days no changes in urinary excretion of PGE2, PGF2 alpha, noradrenaline or adrenaline were noted, whereas plasma renin activity (PRA) and urinary aldosterone excretion were suppressed. After 4 days of low sodium intake (35 mmol/day) urinary excretion of PGE2, aldosterone and noradrenaline, as well as PRA, had significantly increased. Inhibition of PG synthesis with indomethacin (2 mg/kg body weight) had no effects on renal function on day 5 of high sodium intake. Despite suppression of PRA and urinary aldosterone, indomethacin significantly reduced p-aminohippurate (PAH) clearance, glomerular filtration rate (GFR) and urinary sodium excretion on day 5 of low sodium intake, when urinary noradrenaline excretion remained high. The results point to the crucial role of the renal adrenergic nervous system in controlling renal vascular resistance and sodium conservation in healthy subjects during low sodium intake, which is unmasked when renal PG synthesis is blocked by indomethacin. Enhanced renal PG synthesis during sodium restriction therefore not only attenuates the vascular and tubular effects of the renin-angiotensin system but, more importantly, also those of the highly stimulated renal adrenergic nervous system.     

A Micropuncture Study of Potassium Excretion by the Remnant Kidney

In order to study the mechanism of enhanced potassium excretion by the remaining nephrons of the remnant kidney, micropuncture and clearance experiments were carried out in rats after surgical ablation of 3/4 of the total renal mass. The potassium intake in all animals was approximately 5 meq/day. Animals were studied 24 h and 10-14 days after 3/4 nephrectomy. Balance measurements in the chronic animals before micropuncture study indicated that 24 h K(+) excretion by the remnant kidney was equal to that of the two kidneys before ablation of renal mass. Measurements of distal tubular inulin and potassium concentrations revealed progressive reabsorption of potassium in this segment of the nephron in both the 24-h and chronic 3/4-nephrectomized rats, as well as in normal control rats. A large increase in tubular fluid potassium content occurred between the end of the distal tubule and the final urine in the 3/4-nephrectomized rats, but not in the normal controls. These observations suggest that the segment of the nephron responsible for enhanced potassium excretion by remaining nephrons was the collecting duct.In additional experiments, potassium was completely eliminated from the diet of chronic 3/4-nephrectomized rats before micropuncture study. In these animals, no addition of K(+) occurred beyond the distal tubules. Normal rats infused with 0.15 M KCl to acutely elevate serum K(+) concentration, demonstrated reabsorption of K(+) in the distal tubule and a large addition of K(+) to the urine beyond the distal tubule.We conclude that the collecting duct is the major site of regulation of urinary potassium excretion in normal rats and is responsible for the adaptation to nephron loss by the remnant kidney.