Exaggerated natriuretic response to isotonic volume expansion in hypertensive renal transplant recipients: evaluation of proximal and distal tubular reabsorption by simultaneous determination of renal plasma clearanceof lithium and 51Cr-EDTA

In fourteen hypertensive and fourteen normotensive renal transplant recipients, and in a group of thirteen healthy controls, changes in natriuresis, glomerular filtration rate (GFR), and tubular reabsorption of sodium were determined in relation to intravenous infusion of 2 mmol isotonic sodium chloride per kg body weight. An exaggerated natriuresis was demonstrated in the hypertensive renal transplant recipients. This new finding indicates that the augmented natriuresis following plasma volume expansion, which is a characteristic finding in subjects with arterial hypertension, is not mediated by the renal nerves. Investigation of the tubular reabsorption rates of sodium by simultaneous determination of the renal clearance of 51Cr-EDTA and lithium showed that in the hypertensives the changes in tubular handling of sodium were different from those registered in the normotensive subjects. The increased sodium excretion in the hypertensive renal transplant recipients was caused by an increased output of sodium from the proximal tubules which was not fully compensated for by an increased distal reabsorption. Whether this increased delivery of sodium to the distal segments was caused by changes in GFR or in the proximal tubular reabsorption of sodium could not be clarified in the present study and warrants further investigations.     

Renal and hormonal actions of atrial natriuretic peptide during angiotensin II or noradrenaline infusion in man

In order to study the renal and hormonal actions of atrial natriuretic peptide (ANP) during background infusions with angiotensin II (ANG II) or noradrenaline (NA), 69 healthy subjects were examined in three main groups receiving a 90-min infusion with either placebo, ANG II (1.5 ng kg^?1 min^?1), or NA (25 ng kg^?1 min^?1). Each of these three main groups were subdivided into two groups receiving an infusion with either placebo or ANP (10 ng kg^?1 min^?1) for the last 60 min of the background infusion. Lithium clearance was used to evaluate segmental tubular reabsorption. ANG II alone caused a decrease in glomerular filtration rate (GFR), renal plasma flow, urinary absolute and fractional excretion of sodium, both proximal and distal fractional tubular sodium reabsorption, and urinary flow. NA alone caused a decrease in renal plasma flow. ANP alone caused a decrease in renal plasma flow. Urinary absolute and fractional excretion of sodium were increased and the distal fractional tubular reabsorption of sodium decreased, whereas the proximal fractional tubular reabsorption was unchanged by ANP. ANG II + ANP: during a background ANG II infusion, ANP still increased fractional excretion of sodium. Proximal fractional reabsorption was decreased, whereas distal fractional reabsorption of sodium was unchanged by ANP during ANG II infusion. The ANP-induced decreases in proximal absolute (?147 vs. +714 μmol min^?1 1.73 m^?2P = 0.05) and fractional (?1.7% vs. +0.6%, P<0.01) tubular sodium reabsorption were more pronounced, and the decrease in distal fractional tubular reabsorption of sodium (?0.1% vs. ?1.4%, P<0.05) less pronounced compared with when ANP was given alone. NA + ANP: during a background NA infusion, ANP still increased urinary sodium excretion and decreased distal fractional reabsorption. None of the ANP-induced absolute changes seen during background infusion with NA were significantly different from the ANP-induced changes seen during placebo background infusion. It is concluded that the natriuretic action of low-dose ANP seems to be preserved during background infusions with ANG II and NA in man. Net sodium excretion during the combined infusion with ANG II and ANP seems to reflect the sum of the opposing influences of each peptide. Low-dose ANP had a very modest but significant inhibitory effect on proximal tubular sodium reabsorption prestimulated by ANG II infusion.     

Exaggerated phosphaturic response to volume expansion in patients with essential hypertension.

1. Tubular handling of sodium in hypertensive patients has been evaluated with urinary phosphate excretion used as a marker for proximal tubular reabsorptive capacity. 2. Nine hypertensive patients and nine normal control subjects were studied during sustained water diuresis and the intravenous infusion of isotonic sodium chloride solution to produce volume expansion. 3. In the hypertensive patients there was exaggerated phosphaturia, natriuresis and enhanced distal delivery of sodium. Sodium reabsorption in the diluting segment was normal. 4. The enhanced distal delivery and augmented phosphaturia suggest that a decreased reabsorption of sodium in the proximal tubule is the most likely explanation for the exaggerated natriuretic response to volume expansion in hypertensive patients.     

Renal tubular reabsorption of sodium and water during infusion of low-dose dopamine in normal man

1. Using the renal clearance of lithium (CLi) as an index of proximal tubular outflow of sodium and water, together with simultaneous measurements of effective renal plasma flow, glomerular filtration rate (GFR) and sodium clearance (CNa), renal function and the tubular segmental reabsorption rates of sodium and water during dopamine infusion (3 micrograms min-1 kg-1) were estimated in 12 normal volunteers. 2. CNa increased by 128% (P less than 0.001). Effective renal plasma flow and GFR increased by 43% (P less than 0.001) and 9% (P less than 0.01), respectively. CLi increased in all subjects by, on average, 44% (P less than 0.001). Fractional proximal reabsorption [1-(CLi/GFR)] decreased by 13% after dopamine infusion (P less than 0.001), and estimated absolute proximal reabsorption rate (GFR-CLi) decreased by 8% (P less than 0.01). Absolute distal sodium reabsorption rate [(CLi-CNa) x PNa, where PNa is plasma sodium concentration] increased (P less than 0.001), and fractional distal sodium reabsorption [(CLi-CNa)/CLi] decreased (P less than 0.001). 3. It is concluded that natriuresis during low-dose dopamine infusion is caused by an increased outflow of sodium from the proximal tubules that is not fully compensated for in the distal tubules.     

Effect of intravenous sodium loading on renal tubular handling of sodium and water in unilaterally nephrectomized humans

Glomerular filtration rate (GFR), proximal absolute and fractional reabsorption of isotonic fluid (PAR and PFR) and distal absolute and fractional reabsorption of sodium (DARNa and DFRNa) were measured using the lithium clearance technique in nine unilaterally nephrectomized people (UNP) 1-11 years postnephrectomy and in 14 controls before, during and after an intravenous sodium load. Glomerular filtration rate per kidney was 53% higher in UNP and decreased slightly but significantly (p less than 0.01) in both groups during sodium loading. The PAR per kidney was significantly higher in UNP (p less than 0.01) but PFR was the same as in controls. Both groups responded to sodium loading with a significant decrease in both PAR and PFR. In UNP, DARNa per kidney was significantly higher than in controls (p less than 0.01) but DFRNa was the same in the two groups. Sodium loading resulted in a further increase in DARNa and a decrease in DFRNa in both groups. Both groups responded to sodium loading with a similar increase in fractional sodium excretion. It is concluded that unilateral nephrectomy is followed by an increase in GFR, PAR and DARNa but with maintenance of fractional reabsorption in both proximal and distal tubuli. In response to an intravenous sodium load, the remnant kidney is able to respond in a normal way with a further increase in DARNa. The adjustments necessary to maintain sodium balance after unilateral nephrectomy take place in both proximal and distal tubuli.     

Overall renal and tubular function during infusion of amino acids in normal man

1. Amino acids have been used to test renal reserve filtration capacity. Previous studies suggest that amino acids increase glomerular filtration rate (GFR) by reducing distal tubular flow and tubuloglomerular feedback activity. 2. Glomerular function and the renal tubular handling of sodium during infusion of amino acids was studied in 12 normal volunteers. 3. Clearance of sodium (CNa) was unchanged. Effective renal plasma flow increased slightly, but significantly, by 9% (P less than 0.05). GFR was increased by 13% (P less than 0.001). Clearance of lithium (CLi) (used as an index of proximal tubular outflow) increased by 38% (P less than 0.001). Calculated absolute proximal reabsorption (GFR-CLi) remained unchanged. Fractional proximal reabsorption [1-(CLi/GFR)] was decreased by 10% (P less than 0.001). Calculated absolute distal sodium reabsorption [(CLi-CNa) x PNa, where PNa is plasma sodium concentration] increased by 40% (P less than 0.001). Plasma renin concentration did not change significantly. 4. The results suggest that amino acids increase GFR by a primary effect on renal haemodynamics or, less likely, by reducing the signal to the tubuloglomerular feedback mechanism. The increase in proximal tubular outflow was compensated for in the distal tubules, so that the sodium excretion rate remained unchanged.     

Tubular sites of furosemide natriuresis in volume-replaced and volume-depleted conscious rats

There is accumulating evidence that the renal Li clearance reflects the delivery of Na and volume out of the proximal tubules. In the present study we used the Li clearance technique to evaluate the effects of submaximal furosemide (Fur) infusion (7.5 mg/kg/hr) on proximal and distal Na reabsorption in conscious rats with and without volume replacement with saline. Li was given as an p.o. test dose (0.5 mmol/kg) and [3H]inulin was infused in saline to measure the glomerular filtration rate (GFR). In control rats not infused with F, fractional Na excretion was about 1% and fractional Li excretion was about 30 to 35%. Infusion of F with constant rate and volume replacement increased fractional Na excretion to 22% and fractional Li excretion to 57% associated with a small decrease of the GFR. Without volume replacement F infusion caused a smaller and temporary diuretic and natriuretic response (maximum fractional Na excretion = 7.5%) followed by a decrease of urine flow and Na excretion almost to control levels, despite continued high excretion rates of F. The GFR decreased by 25% and fractional Li excretion showed an initial increase followed by return to baseline levels. The results suggest that in conscious rats submaximal doses of F cause major inhibition of proximal tubular Na reabsorption, which effect contributes substantially to the initial natriuresis. Along with diuretic-induced volume contraction, the natriuretic response is abolished due to a fall in GFR and particularly due to a secondary increase in fractional Na reabsorption, which occurs both in proximal distal tubular nephron segments.     

Abnormal glomerular and tubular function during angiotensin converting enzyme inhibition in renovascular hypertension evaluated by the lithium clearance method

Glomerular filtration rate (GFR) and tubular function were measured by means of the lithium clearance technique in 14 patients with renovascular hypertension (RVH) and eight patients with essential hypertension (EH) before and after oral administration of captopril 25 mg. In RVH captopril reduced 51-Cr-EDTA clearance (67.3 (median) to 47.5 ml min-1, P less than 0.01), proximal absolute reabsorption of fluid (53.9 to 41.5 ml min-1, P less than 0.01) and distal absolute reabsorption of sodium (2195 to 1402 mumol min-1, P less than 0.01), whereas proximal fractional reabsorption increased slightly (77.5 to 80.2%, P less than 0.02). In EH, however, these parameters were practically unaffected by captopril. In both RVH and EH plasma concentrations of angiotensin II and aldosterone were reduced after captopril, but atrial natriuretic peptide in plasma and urinary excretion rate of prostaglandin E2 were unchanged. Blood pressure decreased after captopril in both groups, but the maximum fall in systolic BP was more pronounced in RVH (22%) than EH (13%). It is concluded that angiotensin converting enzyme inhibition markedly reduced absolute reabsorption in both the proximal and distal tubules in RVH, in contrast to EH, predominantly due to fall in the GFR, and that the slight increase in proximal fractional reabsorption may be attributed to a reduction in the hydrostatic pressure in the peritubular vessels.     

Effects of insulin on renal haemodynamics and sodium handling in normal subjects

Diabetic patients treated with insulin injected subcutaneously are characterized by peripheral hyperinsulinaemia and an increased mass of total body exchangeable sodium. We hypothesized that this may cause, at least in part, the glomerular hyperfiltration seen in the diabetic state. Six normal subjects were studied on 2 days in random order. Day A: Basal state for 40 min, hyperinsulinaemic euglycaemic clamp for 1 h (insulin infusion rate 2 mU kg-1 min-1 and 50% glucose infusion) and hyperinsulinaemic euglycaemic clamp combined with volume expansion (2 1 isotonic sodium chloride) for 2 h. Day B: as day A, but without insulin and glucose infusion. During combined volume expansion and hyperinsulinaemia an increase in glomerular filtration rate (GFR) (128 +/- 6 vs 117 +/- 8 ml min-1 1.73 m-2, p less than 0.01) and lithium clearance (CLi) (50 +/- 4 vs 33 +/- 5 ml min-1 1.73 m-2, p less than 0.01) was observed compared with basal conditions. GFR and CLi were unchanged during day B. Insulin infusion reduced renal sodium excretion. Absolute proximal tubular reabsorption was unchanged on both days. Insulin infusion without volume expansion caused a decrease of 24% in the fractional distal sodium excretion. Superimposed volume expansion and the concomitant increase in GFR and CLi was accompanied by a subsequent enhanced fractional distal sodium excretion of 27%. The changes in plasma concentrations of aldosterone, renin, angiotensin II, atrial natriuretic peptide and catecholamines did not explain the differences in GFR. An increase in GFR of 10%, comparable with that observed in diabetic patients, was induced by combined hyperinsulinaemia and volume expansion in euglycaemic normal subjects. The enhanced GFR is probably a compensatory response to the sodium retention induced by the action of insulin on the distal tubules.     

Renal water and sodium handling in compensated liver cirrhosis: mechanism of the impaired natriuresis after saline loading

The present study was attempted to evaluate sodium and water balance in compensated liver cirrhosis. Renal sodium and water handling was studied in six cirrhotic patients without ascites and/or oedema and in six controls before and after saline loading. Fractional sodium reabsorption at the various nephron sites (proximal, diluting and distal) was evaluated by means of clearance techniques during maximal water diuresis and hypotonic saline infusion. Compensated cirrhotic patients showed a normal baseline sodium and water balance but a blunted natriuretic response when saline loaded (urinary sodium excretion after saline load = 338 +/- 290 compared to 933 +/- 504 mumol min-1 of controls; P less than 0.05). The impaired natriuresis was found to be related to an increased reabsorption of sodium in the proximal tubule (proximal fractional sodium reabsorption = 88.4 +/- 3.8 compared to 81.7 +/- 4.3% of controls; P less than 0.05). These findings confirm the hypothesis that renal sodium handling abnormalities might precede ascites formation. Additional studies, however, are necessary to further define renal factors mediating the increased reabsorption of sodium in compensated liver cirrhosis.     

Effects of verapamil alone and with captopril on blood pressure and bilateral renal function in Goldblatt hypertensive rats

The effects of verapamil infusion alone and superimposed with captopril on arterial pressure and bilateral renal function were evaluated in 21 two-kidney, one-clip Goldblatt hypertensive rats and in 13 control rats. Verapamil significantly decreased arterial pressure of both hypertensive and control rats. Addition of captopril further reduced arterial pressure in hypertensive rats only. There were significant increases in glomerular filtration rate (GFR), urine flow and absolute and fractional excretory rates of sodium and potassium in the non-clipped kidney. In contrast, these renal indices decreased in the clipped kidney. Superimposed captopril during verapamil infusion did not significantly change function of the non-clipped kidney but further depressed function of the clipped kidney. In control rats, no significant change in GFR occurred in response to drugs. Renal excretion of water and sodium, but not potassium, increased after verapamil. However, the diuresis and natriuresis were less pronounced than those seen in the non-clipped kidney of hypertensive rats. There was a proportionate increase in osmolar clearance and free water reabsorption rate in the non-clipped kidney and the normal kidney. The linear relationship did not change after verapamil infusion. The results suggest that verapamil enhances the excretory function of the non-clipped kidney of Goldblatt hypertensive rats via increased GFR and decreased tubular reabsorption in the proximal and/or distal tubules despite its hypotensive action.     

A Comparison of the Segmental Analysis of Sodium Reabsorption during Ringer''s and Hyperoncotic Albumin Infusion in the Rat

Studies were designed to compare the segmental analysis of sodium reabsorption along the nephron during volume expansion with either 10% body weight Ringer's or 0.6% body weight hyperoncotic albumin. Total kidney and nephron glomerular filtration rate increased similarly with both, but urinary sodium excretion (12.7 vs. 4.0 mueq/min, P < 0.001) and fractional sodium excretion (5.0 vs. 1.6%, P < 0.001) increased to a greater extent with Ringer's. Fractional reabsorption of sodium in the proximal tubule was diminished in both groups but to a significantly greater extent during Ringer's (P < 0.005). Absolute reabsorption was inhibited only in the Ringer's group. Delivery of filtrate out of the proximal tubule was greater in the Ringer's studies, 45 vs. 37 nl/min (P < 0.001). However, both fractional and absolute sodium delivery to the early and late distal tubule were not significantly different in the two groups. Fractional reabsorption in the collecting duct decreased from 96% in hydropenia to 31% during Ringer's but fell only slightly to 80% in the albumin studies. Absolute collecting duct reabsorption was also greater in the albumin studies, 0.55 vs. 0.21 neq/min (P < 0.001), which could totally account for the difference in urinary sodium excretion between the two groups. (22)Na recovery in the final urine after end distal microinjections was 71% during Ringer's infusion and 34% during albumin (P < 0.001). From these data we conclude that: (a) Ringer's solution has a greater inhibitory effect on proximal tubular sodium reabsorption, and (b) in spite of this effect, differences in mucosal to serosal collecting duct sodium transport are primarily responsible for the greater natriuresis during Ringer's infusion.     

Effects of Felodipine on the dog kidney: a lithium clearance study.

This study was performed in order to investigate the possible influence of sympathetic nerve activity on the effects of the dihydropyridine calcium antagonist felodipine on absolute and fractional reabsorption rates of sodium and water in proximal and distal tubular segments in the dog kidney. Clearance of 51Cr-EDTA was used as a measure of glomerular filtration rate (GFR). GFR, urinary excretion rates of sodium and water, and lithium clearance (C-Li) were used for assessing the absolute and fractional tubular reabsorption rates. Felodipine infusion into the right renal artery increased renal vascular conductance (renal blood flow divided by renal arteriovenous pressure gradient) significantly (by 9%) while GFR remained unchanged. Calculated absolute proximal reabsorption rates remained unchanged while distal sodium reabsorption rate increased significantly from 2.1 +/- 0.3 to 2.7 +/- 0.4 mmol min-1. Sodium clearance (C-Na) increased from 0.22 +/- 0.08 to 0.40 +/- 0.07 ml min-1. The alpha-adrenergic blockade with phentolamine did not affect renal haemodynamic or excretory variables, nor did it influence the haemodynamic response to felodipine. After alpha-adrenergic blockade felodipine caused an increase in C-Na from 0.28 +/- 0.06 ml min-1 to 0.63 +/- 0.04 ml min-1, which was significantly greater than that measured after felodipine alone. The distal load (C-Li) was not significantly different from that obtained after felodipine alone, but distal sodium reabsorption rate increased less significantly after alpha-adrenergic blockade. The results suggest that felodipine, by its effect on tubular flow and/or composition, activates local alpha-adrenergic reflex mechanism(s), which stimulates distal sodium reabsorption, thereby attenuating the natriuretic effect.     

The relative contributions of reabsorptive rate and redistributed nephron filtration rate to changes in proximal tubular fractional reabsorption during acute saline infusion and aortic constriction in the rat

The absolute rate of reabsorption by superficial rat proximal tubules was measured by the in situ microperfusion technique under conditions of hydropenia, infusion of saline, and infusion of saline plus aortic constriction sufficient to decrease whole kidney filtration rate below hydropenic levels. Fractional reabsorption was measured in adjacent filtering nephrons by collecting and recollecting tubular fluid from late proximal convolutions during each experimental condition. During hydropenia, the absolute rate of proximal tubular reabsorption averaged 3.56 +/-0.60 nl/min per mm and late proximal tubular fractional reabsorption averaged 0.56 +/-0.10. From these two measurements and measurements of tubule length to the site of micropuncture, a value for filtration rate was calculated for filtering nephrons. During hydropenia this value averaged 32.9 +/-7.1 nl/min. Saline infusion increased sodium excretion to 5.5% of the filtered load as the absolute rate of proximal tubular reabsorption decreased 38% and fractional reabsorption decreased 45%. Calculated superficial nephron filtration rate increased 21% which on the average was identical with the simultaneously measured increase in whole kidney filtration rate. Similar results were obtained in a separate group of animals by the technique of total collection of late proximal tubular fluid. Aortic constriction during saline infusion decreased whole kidney and calculated nephron filtration rate to the same degree and to values lower than those during hydropenia. Fractional reabsorption increased but not to hydropenic values. The persistent natriuresis during aortic constriction was associated with a continued depression of the absolute rate of proximal tubular reabsorption which was sufficient to maintain an increased delivery of filtrate out of the proximal tubule despite the fall in nephron filtration rate. These results indicate that depressed fractional reabsorption in the proximal tubule during acute saline infusion is due predominantly to a decrease in absolute reabsorptive rate and to a lesser extent to an increase in superficial nephron filtration rate which is proportional to the increase in whole kidney filtration. Continued natriuresis when filtration rate is decreased during saline infusion can be accounted for entirely by the persistent large reduction in the absolute rate of proximal tubular reabsorption.     

The syndrome of hypertension and hyperkalemia with normal GFR (Gordon's syndrome): is there increased proximal sodium reabsorption?

The syndrome of hypertension and hyperkalemia, hyperchloremic acidosis with normal glomerular filtration rate (Gordon's syndrome) is characterised by volume expansion, suppressed renin and reduced mineralocorticoid-induced renal clearance of potassium. The clinical and biochemical defects are aggravated by high salt diet and corrected by low salt diet, leading to the hypothesis of excessive sodium reabsorption in the nephron proximal to where aldosterone acts. In this study, we used lithium clearance as a marker of proximal sodium reabsorption in three patients with Gordon's syndrome, in order to further localise the site in the nephron of defective sodium handling. Fractional excretion of lithium was decreased, and absolute and fractional proximal reabsorption of sodium was increased compared to normal controls. In addition, absolute distal reabsorption of sodium was decreased, consistent with decreased mineralocorticoid activity. Fractional excretion of potassium was markedly decreased and did not rise with increased distal delivery of sodium during saline infusion. However, after severe dietary sodium restriction had elevated plasma aldosterone (lowering plasma potassium levels to normal), fractional excretion of potassium was raised by saline infusion. Reduced lithium clearance in patients with Gordon's syndrome supports the hypothesis of increased proximal sodium reabsorption in this condition.     

Tubular handling of sodium and phosphate in non-ascitic liver cirrhosis

The renal response to a maximal water load was evaluated in eight cirrhotic patients free of ascites and without previous evidence of ascites and in seven controls. Fractional sodium reabsorption in the proximal and diluting segment was estimated by clearance methods during hypotonic diuresis. Since phosphate excretion has been proposed as a proximal marker in liver cirrhosis, sodium reabsorption in the proximal tubule was compared with phosphate fractional excretion. In spite of a normal sodium balance during the pre-study period, non-ascitic cirrhotics showed a blunted proximal natriuretic response to maximal water load. In fact sodium excretion during hypotonic diuresis was reduced (p less than 0.05) and proximal sodium reabsorption increased (p less than 0.005) in cirrhotics. Fractional phosphate excretion was not impaired in our patients, and no correlation was found between phosphate excretion and proximal sodium reabsorption, as evaluated by clearance methods. This study demonstrates that an increased reabsorption of sodium in the proximal tubule is responsible for the impaired response to maximal water load in non-ascitic cirrhotics. Abnormalities in tubular handling of phosphate may account for the dissociation between proximal sodium reabsorption and phosphate excretion during hypotonic diuresis in these patients.     

The diuretic effect of calcium entry blockade in normals and hypertensive patients.

Calcium entry blockers have been shown to exert hemodynamic and diuretic effects in the kidney. The diuretic effects can be demonstrated most clearly in the isolated perfused kidney, not influenced by compensatory mechanisms such as a lower blood pressure or changes of hormones. However, they can also be shown in vivo in humans. We studied the renal effects of calcium entry blockade after the first dosage and after continued oral dosages of 20 mg nicardipine tid in patients with essential hypertension and in normotensive controls. Renal function was determined during maximal free water clearance, allowing estimation of changes in "proximal" and "distal" tubular sodium reabsorption. Results showed a natriuretic effect. In the control subjects, clearance results were compatible with a decrease of proximal and distal tubular reabsorption, but in the hypertensive group natriuresis was mainly achieved by an increase of the glomerular filtration rate and a decrease of fractional distal reabsorption. In both groups the natriuresis occurred concomitantly with a lower blood pressure. The ratio plasma renin activity/plasma aldosterone concentration increased, although nicardipine did not inhibit the increase of plasma aldosterone during angiotensin II infusion. Pre-treatment with the calcium entry blocker nitrendipine enhanced the natriuretic effect of atrial natriuretic factor (ANF) in sodium replete normal volunteers. Facilitation of sodium excretion by human ANF may be an additional diuretic mechanism of calcium entry blockers.     

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.     

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 effects of glucose and insulin on renal electrolyte transport.

The effects of hyperglycemia and hyperinsulinemia on renal handling of sodium, calcium, and phosphate were studied in dogs employing the recollection micropuncture technique. Subthreshold sustained hyperglycemia resulted in an isonatric inhibition of proximal tubular sodium, fluid, calcium, and phosphate reabsorption by 8-14%. Fractional excretion of sodium and phosphate, however, fell (P is less than 0.01) indicating that the increased delivery of these ions was reabsorbed in portions of the nephron distal to the site of puncture and in addition net sodium and phosphate transport was enhanced resulting in a significant antinatriuresis and antiphosphaturia. The creation of a steady state plateau of hyperinsulinemia while maintaining the blood glucose concentration of euglycemic levels mimicked the effects of hyperglycemia on proximal tubular transport and fractional excretion of sodium and calcium. Tubular fluid to plasma insulin ratio fell, similar to the hyperglycemic studies. These results suggest that the effects of hyperglycemia on renal handling of sodium and calcium may be mediated through changes in plasma insulin concentration. In contrast to hyperglycemia, however, hyperinsulinemia cuased a significant fall in tubular fluid to plasma phosphate ratio with enhanced proximal tubular phosphate reabsorption (P is less than 0.02). This occurred concomitantly with a significant inhibition of proximal tubular sodium transport. These data indicate that insulin has a direct effect on proximal tubular phosphate reabsorption, and this effect of insulin is masked by the presence of increased amounts of unreabsorbed glucose in the tubule that ensues when hyperinsulinemia occurs secondary to hyperglycemia. Fractional excretion of phosphate fell significantly during insulin infusion but unlike the hyperglycemic studies, the fall in phosphate excretion could be entirely accounted for by enhanced proximal reabsorption.