Fractional Distal Sodium Reabsorption Research Articles

Stimulatory effect of insulin on tubular sodium reabsorption in normotensive subjects with a positive family history of hypertension

Insulin resistance and hyperinsulinaemia has been suggested as a pathogenetic mechanism in hypertension. In this investigation the renal response to insulin was studied in normotensive subjects with a positive family history of hypertension in two generations (n = 14), in one weight-matched (n = 11) and one lean (n = 13) control group. During hyperinsulinaemia (euglycaemic hyperinsulinaemic clamp technique) we determined renal haemodynamics (clearances of 51Cr-EDTA and PAH) and urinary sodium excretion. Lithium clearance was used to estimate the segmental tubular reabsorption of sodium. In subjects with a positive family history of hypertension, hyperinsulinaemia did not influence renal plasma flow (RPF) or glomerular filtration rate (GFR) but urinary sodium excretion decreased by 50%. Estimated proximal tubular sodium reabsorption was unaffected by insulin while estimated distal fractional sodium reabsorption increased, P < 0.01. At the end of the clamp a low-dose infusion of angiotensin II (0.1 ng/kg per min) was superimposed. GFR and RPF then decreased significantly concomitant with urinary excretion of sodium. In control subjects hyperinsulinaemia caused an unchanged GFR in both groups, increased RPF in the lean control group and 15-25% reduction in sodium excretion. No alteration was seen in estimated proximal tubular sodium reabsorption, but estimated distal tubular sodium reabsorption increased (P < 0.05) in the lean control group. Angiotensin II elicited a further increase in distal fractional tubular sodium reabsorption in both groups (P < 0.05). In normotensive subjects with a positive family history of hypertension, in contrast to control subjects without such history, hyperinsulinaemia caused a marked decrease in urinary sodium excretion in presence of unchanged RPF and GFR indicating a renal tubular effect of insulin located at distal site of the renal tubules. Angiotensin II caused further sodium retention, probably due to an effect on renal haemodynamics.

Acute Effects of Physiological Increments of Brain Natriuretic Peptide in Humans

To investigate the effects of physiological increases in plasma brain natriuretic peptide concentration in humans, we studied six healthy volunteers who received incremental infusions (0.25 pmol/kg per minute in the first hour and 0.50 pmol/kg per minute in the second) of synthetic human brain natriuretic peptide-32 in a placebo-controlled, crossover study. Peptide plasma levels were 1.69 +/- 0.39 pmol/L at baseline and rose 1.5- and 3-fold with the lower and higher doses, respectively. These values were within the normal range and also comparable to those reported in patients with mild essential hypertension. The urinary excretion rate of cGMP also increased during brain natriuretic peptide infusion, indicating stimulation of natriuretic peptide receptors. Peptide administration induced a significant 1.7-fold increase in urinary sodium excretion without affecting renal plasma flow (para-aminohippurate clearance), glomerular filtration rate (creatinine clearance), and urine flow rate. Fractional proximal sodium reabsorption (lithium clearance method) was unchanged, and fractional distal sodium reabsorption significantly decreased. Brain natriuretic peptide caused no changes in arterial pressure, heart rate, hematocrit, and serum proteins, but it exerted an inhibitory effect on the renin-aldosterone axis, as indicated by the significant 50% or more decrease of plasma renin activity and urinary excretion rate of aldosterone. These results suggest that brain natriuretic peptide may be involved in the overall regulation of body fluid and cardiovascular homeostasis in humans, mainly through its natriuretic and endocrine effects.

Glomerular Filtration Rate and Segmental Tubular Function in the Early Phase after Transplantation/Uninephrectomy in Recipients and Their Living-Related Kidney Donors

1. Glomerular filtration rate and sequential tubular function were investigated in 18 adult renal transplant recipients and in their matched, adult living-related kidney donors before and 5 days after transplantation/uninephrectomy. At day 54, 13 donors and 11 recipients were re-investigated. Sixteen of these constituted eight matched pairs. This reduction in the study population was caused by the application of two withdrawal criteria. 2. In the recipients glomerular filtration rate was unchanged at day 5 and had increased to 61 ml/min at day 54 (P < 0.05). In the donors glomerular filtration rate had increased to 59 ml/min by day 5 (P < 0.01) and was unchanged at day 54. 3. In the recipients lithium clearance was unchanged at day 5 and had increased to 23 ml/min at day 54 (P < 0.01). In the donors the lithium clearance had increased by day 5 (P < 0.01). 4. In the recipients the absolute proximal fluid reabsorption rate was about 36 ml/min throughout the study period. In the donors the absolute proximal fluid reabsorption rate had increased to 42 ml/min by day 5 (P < 0.05) and increased further to 44 ml/min by day 54 (P < 0.01). 5. In the recipients sodium clearance increased from 0.54 ml/min to 2.10 ml/min at day 54 (P < 0.01). In the donors it increased from 0.64 ml/min to 0.99 ml/min at day 54 (P < 0.05). 6. Donor-recipient comparison showed that at day 54 there was no significant difference with regard to glomerular filtration rate, lithium clearance, absolute and fractional proximal fluid reabsorption rate and absolute distal sodium reabsorption rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Insulin on Sodium Reabsorption in Hypertensive Patients

The effect of insulin on sodium reabsorption was studied with the hyperinsulinemic euglycemic clamp technique, using lithium clearance as a marker of sodium reabsorption in the proximal tubule. The subjects were 12 nondiabetic hypertensive patients who were divided into two groups. In the first group, the effect of insulin on sodium and lithium reabsorption was examined. The second group served as a control. Blood glucose was continuously monitored from 9 AM to 10 AM (baseline period). Hyperinsulinemic euglycemic clamp was performed with an artificial endocrine pancreas by infusing insulin at a rate of 2 mU/kg.min from 10 AM to noon. In the control group the protocol was exactly the same except that glucose clamp was not performed. Urine was collected hourly from 9 AM to noon. In the glucose clamp group, urinary sodium excretion (UNaV) decreased by 42% during the second hour of the glucose clamp (P < .02). Clearance of lithium (CLi) and fractional distal sodium reabsorption [(CLi-CNa)/CLi] increased, and CNa/CLi decreased significantly during the glucose clamp. In the control group, UNaV and (CLi-CNa)/CLi remained unchanged, and CLi decreased significantly. As shown by the increase of CLi and (CLi-CNa/CLi, and the decrease of UNaV and CNa/CLi in the glucose clamp group, insulin decreases urinary sodium excretion by increasing distal sodium reabsorption, whereas it inhibits sodium reabsorption in the proximal tubule.

Biological actions of brain natriuretic peptide in thoracic inferior vena caval constriction.

Brain natriuretic peptide (BNP) shares structural and functional similarities to atrial natriuretic peptide (ANP). Although BNP and ANP interact with the same biologically active guanylate cyclase-coupled receptor, recent reports conflict with regard to the biological actions of exogenous BNP in sodium-retaining and edematous states. We studied the biological actions of BNP in normal dogs (n = 5) and sodium-avid dogs with chronic thoracic inferior vena caval constriction (TIVCC) (n = 6). In normal dogs BNP increased glomerular filtration rate, renal blood flow, and urinary sodium excretion and decreased proximal and distal fractional reabsorption of sodium with activation of urinary guanosine 3',5'-cyclic monophosphate (cGMP). These renal actions occurred in association with marked hypotensive actions and activation of systemic cGMP. In TIVCC, a state characterized by chronic reductions of cardiac output, avid sodium retention, edema, and activation of the renin-angiotensin-aldosterone system (RAAS), the renal actions of BNP were absent in association with marked attenuation of the urinary cGMP response. In contrast, an enhanced hypotensive response with preserved activation of systemic cGMP was observed. In neither normal dogs nor TIVCC dogs did BNP inhibit the RAAS. These studies report that BNP is a potent vasoactive and natriuretic peptide with potent proximal and distal tubular actions in normal dogs. These studies also demonstrate that in TIVCC, a model of low cardiac output and congestive failure that results in marked sodium retention with edema in which there is activation of the RAAS, the renal actions of BNP are attenuated while the vasoactive actions are enhanced.

Atrial natriuretic factor counteracts sodium-retaining actions of insulin in normal men

It has been hypothesized that hyperinsulinemia is causally related to hypertension by its effect on renal sodium transport. To examine the relationship between the sodium-retaining actions of insulin and atrial natriuretic factor (ANF), 16 healthy subjects were studied on three occasions, approximately 1 wk apart, using standard clearance techniques to evaluate responses during the acute administration of insulin, low-dose ANF, or both. In study 1, the euglycemic clamp was used to increase plasma insulin 10-fold to an average of 320 +/- 14 (SE) pM. This maneuver produced an immediate and persistent fall in sodium excretion from 0.315 +/- 0.02 to 0.207 +/- 0.02 mmol/min (P < 0.001) independent of change in renal hemodynamics, lithium clearance, and catecholamines. The decline in sodium excretion was associated with a marked increase in fractional distal sodium reabsorption. Systolic and diastolic pressure did not change significantly. In study 2, low-dose ANF (0.3 pmol.kg-1.min-1) designed to raise plasma levels to twice baseline was administered simultaneously in a repeat of study 1. This maneuver abolished insulin-mediated sodium reabsorption. In study 3, low-dose ANF infusion alone produced no changes in tubular handling of sodium. Our findings indicate that insulin at levels found in hyperinsulinemic states caused sodium retention and that physiological increases in plasma ANF concentration abolished the sodium-retaining action of insulin. Our findings suggest that if hypertension is causally related to hyperinsulinemia, mechanisms besides renal sodium retention are responsible for the hypertensive properties of insulin.

Tubular handling of fluid and electrolytes during ovine pregnancy

Pregnancy is characterized by progressive water and sodium accumulation and increases in renal blood flow (RBF) and glomerular filtration rate (GFR). However, the influence of the different nephron segments on the increased tubular reabsorption is controversial. Consequently, four nonpregnant and five pregnant sheep were studied, after chronic instrumentation, to assess salt and water reabsorption in the proximal and distal tubules under basal and volume-loaded conditions. Lithium clearance was used as a marker for proximal tubular reabsorption. Volume loading was achieved by the rapid administration of 1,000 ml isotonic saline followed by 250 ml/h for 2 h. Under basal conditions with reference to the nonpregnant state, pregnant sheep had higher (P < 0.05) levels of right RBF (427 +/- 34 vs. 313 +/- 8 ml/min), GFR (133 +/- 7 vs. 94 +/- 9 ml/min), proximal tubular reabsorption (102 +/- 7 vs. 73 +/- 6 ml/min), distal nephron fluid delivery (31 +/- 2 vs. 20 +/- 2 ml/min), and fractional distal nephron reabsorption of fluid (92 +/- 2 vs. 87 +/- 1%) and sodium (98.8 +/- 0.3 vs. 97.0 +/- 0.7%). However, pregnant animals had significantly (P < 0.05) reduced fractional excretions of fluid (1.6 +/- 0.3 vs. 2.6 +/- 0.2%) and sodium (0.24 +/- 0.06 vs. 0.63 +/- 0.19%), but similar levels of filtration fraction, fractional proximal tubular reabsorption, urine flow, urinary sodium excretion, and osmolar and free water clearance. After saline loading, pregnant sheep excreted significantly (P < 0.05) less sodium (9.2 vs. 28.6%) and water (39.8 vs. 56.5%). Decreases in fractional proximal and distal nephron reabsorption of sodium and water after saline loading were attenuated in pregnant animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Tubular Site of the Natriuresis After Unilateral Nephrectomy in the Rat

Unilateral nephrectomy (UNX) is followed by a prompt increase in sodium excretion from the remaining kidney. Recently, an important role for atrial natriuretic peptide (ANP) in mediating the UNX-associated natriuresis has been suggested. The present studies were undertaken to gain insight into the intrarenal mechanisms participating in the post-UNX natriuresis in circumstances in which the release or the action of endogenous ANP were suppressed by prior removal of the right atrial appendage and by administration of monoclonal anti-ANP antibodies, respectively. In anesthetized euvolemic untreated rats, UNX resulted in a twofold increase in urinary excretion of sodium (from 0.93 +/- 0.23 to 2.14 +/- 0.34 microE/min; p < 0.03), whereas glomerular filtration rate did not change significantly. Fractional excretion of lithium, an index of proximal tubular handling of sodium, increased from 30.7 +/- 3.4% to 39.4 +/- 4.0%, and fractional distal reabsorption of sodium decreased from 98.6 +/- 0.2% to 96.5% +/- 0.4% (both p < 0.006). Neither sham atrial appendectomy nor the administration of nonspecific antibodies affect the natriuretic response of the remaining kidney. The natriuretic response to UNX was abolished in right atrial appendectomized rats, as well as in rats receiving anti-ANP antibodies. Post-UNX changes in both proximal and distal tubular reabsorption of sodium were also suppressed in these animals. These observations indicate that ANP may be an important mediator of the natriuretic response to UNX and that the proximal and the distal part of the nephron contribute to the postnephrectomy natriuresis.

Glomerular and tubular antinatriuretic actions of low-dose angiotensin II infusion in man

The aim was to study the physiological effects of angiotensin II upon the glomerular and tubular handling of sodium. Healthy volunteers were examined before and during infusion with either low-dose angiotensin II (n = 11) or placebo (n = 13). Lithium clearance was used to estimate the segmental tubular reabsorption of sodium. During infusion with angiotensin II a sustained and marked fall in renal plasma flow was observed. The glomerular filtration rate (GFR) decreased to a minor extent so that the filtration fraction increased during angiotensin II infusion. Angiotensin II caused an extensive and instantaneous fall in both urinary flow and urinary sodium excretion. Proximal absolute reabsorption of sodium was unchanged despite the fall in GFR, showing that proximal fractional reabsorption was enhanced by angiotensin II. Distal absolute reabsorption was decreased during the entire period of angiotensin II infusion. However, when the distal reabsorption was related to the delivery of sodium from the proximal tubules, distal fractional reabsorption in fact increased after 30 min angiotensin II infusion. None of the measured parameters changed during infusion with placebo. A significant increase in plasma aldosterone was observed 30 min after the start of the angiotensin II infusion. Plasma atrial natriuretic peptide did not change during infusion with either angiotensin II or placebo. We conclude that physiological increments in angiotensin II affect glomerular haemodynamics and cause a marked antinatriuresis in man. The antinatriuretic effect of angiotensin II is caused initially by a combination of a decrease in the GFR and an increase in proximal fractional sodium reabsorption, and later by the enhanced distal fractional reabsorption of sodium.

The role of endogenous angiotensin II in the regulation of renal haemodynamics and proximal fluid reabsorption in the rat.

1. The influence of endogenous angiotensin II (AII) on renal haemodynamics and tubular function was examined by clearance and micropuncture methods in anaesthetized rats during AII receptor blockade with the non-peptide antagonist DuP 753 (50 micrograms kg-1 min-1 i.v.). 2. Mean arterial pressure was reduced slightly (-5 +/- 2 mmHg) while filtration fraction and glomerular filtration rate rose by 30% without changes in renal plasma flow (RPF) or renal vascular resistance (RVR). 3. Fractional proximal fluid reabsorption (calculated from lithium clearance) fell from 73 to 64% (P < 0.01) and fractional distal sodium reabsorption decreased from 98 to 94% (P < 0.01). 4. Urine flow rate more than doubled, sodium output increased 4-fold and plasma renin concentration rose 8-fold while potassium excretion remained unchanged. 5. Proximal tubular fluid reabsorption (Jv) as measured by shrinking split-droplet micropuncture decreased by 21% (P < 0.01) during infusion of DuP 753 compared with 22.5% (P < 0.01) during converting enzyme inhibition by enalaprilat (MK422). 6. Responses to DuP 753 were similar to those previously documented with converting enzyme inhibitors except that DuP 753 failed to raise RPF. It is concluded that generation of intrarenal vasodilator paracrines has confounded conclusions about the renal action of converting enzyme inhibitors and we propose that in anaesthetized rats, endogenous angiotensin II (AII) has its major renal influences on glomerular filtration and proximal fluid reabsorption with little effect on renal vascular resistance.

Effect of Felodipine on Renal Haemodynamics and Tubular Sodium Handling in Cyclosporin-Treated Renal Transplant Recipients

The effect of a single oral dose of 10 mg of the calcium antagonist felodipine or placebo was investigated in 10 cyclosporin-treated renal transplant recipients before, during, and after an acute intravenous infusion of cyclosporin in a randomised, single-blind cross-over study. Renal plasma flow (RPF), glomerular filtration rate (GFR), renal tubular sodium and water handling as judged by the lithium clearance technique, and plasma concentrations of angiotensin II (AngII), aldosterone (Aldo), atrial natriuretic factor (ANF), and arginine vasopressin (AVP) were measured. Both RPF and GFR increased after felodipine (mean increase: RPF, 38.7%; GFR, 16.2%; P less than 0.01 for both) in spite of a significant decrease in both systolic and diastolic blood pressure (mean decrease 10.6% and 16.0% respectively, P less than 0.02 for both). Estimated by the lithium clearance technique felodipine induced a decrease in fractional reabsorption in the proximal tubules (mean 72.0% vs 63.0%, P less than 0.01), an increase in proximal output of fluid (mean 11.0 ml/min vs 16.0 ml/min, P less than 0.01), and a decrease in distal fractional reabsorption of sodium (mean 90.5% vs 83.9%, P less than 0.05) resulting in a significant natriuresis and diuresis. Ang II, Aldo, ANF, or AVP did not change. Intravenous infusion of cyclosporin per se did not influence any of the parameters. It is concluded that a single dose of felodipine in cyclosporin treated renal transplant recipients has beneficial effects on blood pressure, renal haemodynamics, and renal tubular sodium and water handling, which seems to compensate for some of the adverse effects of cyclosporin. It is suggested that these effects result from a direct vasodilatation and an effect on proximal tubular function.

Renal sites of action of physiological increases in plasma atrial natriuretic factor concentration in essential hypertension.

To investigate the renal, haemodynamic and neurohormonal responses to low-dose infusions of atrial natriuretic factor (ANF) in hypertensive humans. Ten patients with mild-to-moderate essential hypertension received incremental infusions of 3 and 6 ng/kg per min ANF or vehicle alone whilst on a constant dietary sodium intake. A 90-min basal clearance period was followed by two 2-h infusion periods, with urine collection in the last 90 min of each period. In each of the three clearance periods, glomerular filtration rate (GFR), renal tubular function, and the activity of the renin-angiotensin and sympathetic nervous systems were determined. The renal sites of ANF action were established by simultaneous measurements of 51Cr-ethylenediaminetetraacetate lithium and sodium clearances. Plasma concentrations of neurohormones were measured by radioimmunoassays. Plasma ANF concentrations increased by 1.6- and 2.5-fold during the lower and higher ANF infusion rates, respectively. Plasma cyclic guanosine monophosphate concentrations increased in parallel. ANF caused no changes in supine systolic and diastolic blood pressure or in heart rate. In contrast, haematocrit values increased progressively across the study. The renal effects of ANF administration were characterized by an unaltered GFR and significant increases in the renal clearances of lithium (a marker of end-proximal fluid delivery) and sodium when compared with vehicle infusions, whereas urine flow did not change. Estimated values of fractional proximal and distal tubular sodium reabsorption decreased significantly. Plasma concentration of active renin decreased during ANF infusions, but no significant changes in plasma levels of renin substrate, angiotensin I, angiotensin II or aldosterone were observed. A subtle activation of the sympathetic nervous system was indicated by a moderate increase in plasma noradrenaline during the ANF infusions. These results indicate that even small increases in plasma ANF, as can be found during physiological conditions, induce natriuresis in patients with essential hypertension by enhancing fluid delivery from the proximal tubules, in addition to impairing distal fractional sodium reabsorption. With minor exceptions, the ANF infusions caused qualitatively and quantitatively similar renal, haemodynamic and endocrine effects in the hypertensive patients as in a previously studied group of normotensive subjects.

Renal and hormonal effects and tolerance of an ANP analogue in healthy man

The effect of an analogue of atrial natriuretic peptide (P-ANP) on glomerular filtration rate (GFR), renal plasma flow (RPF), urinary flow rate, urinary sodium excretion, tubular function estimated by the lithium clearance technique, and plasma levels of sodium and water homeostatic hormones, has been studied in 40 healthy males. Placebo or P-ANP 0.3, 1.5, or 3.0 micrograms.kg-1 bwt were given as an intravenous bolus injection to different groups. P-ANP did not cause any immediate change in GFR or RPF, but significant dose-dependent increases in filtration fraction, urinary flow rate and urinary excretion rate of sodium were detected during the first 30 min after administration. Proximal absolute and fractional tubular reabsorption and distal absolute tubular reabsorption of sodium did not change after injection of P-ANP, while the distal fractional reabsorption of sodium was reduced in a dose dependent manner during the first 30 min. Plasma angiotensin II and aldosterone were significantly increased 30 and 150 min after dosage, whereas plasma atrial natriuretic peptide, plasma arginine vasopressin, and urinary excretion of prostaglandin E2 were unchanged. Cyclic guanosine monophosphate both in plasma and urine were increased in a dose-dependent manner. P-ANP cause a significant reduction in diastolic blood pressure and an increase in pulse rate. Two subjects had vasovagal syncope 30-60 min after injection of P-ANP. It is concluded that P-ANP has natriuretic, diuretic and hypotensive properties in healthy man.

Effect of Inhibition of Converting Enzyme on Renal Hemodynamics and Sodium Management in Polycystic Kidney Disease

We compared the tubular transport of sodium and the erythrocyte sodium-lithium countertransport activity in hypertensive patients with autosomal dominant polycystic kidney disease (ADPKD) and in normotensive control subjects. In addition, we assessed the effects of inhibition of converting enzyme on renal hemodynamics and sodium excretion in hypertensive patients with ADPKD to provide information on mechanisms responsible for the increased renal vascular resistance and filtration fraction and the adjustment of the pressure-natriuresis relationship during saline expansion, observed in patients with ADPKD, hypertension, and preserved renal function. In comparison with normotensive control subjects, the hypertensive patients with ADPKD had lower renal plasma flows, higher renal vascular resistances and filtration fractions, and similar proximal and distal fractional reabsorptions of sodium. The administration of enalapril resulted in significant increases in the renal plasma flow and significant reductions in mean arterial pressure, renal vascular resistance, and filtration fraction, but the glomerular filtration rate remained unchanged. Despite the significant reduction in mean arterial pressure during inhibition of converting enzyme, the distal fractional reabsorption of sodium decreased while the total fractional excretion of sodium remained unchanged or increased slightly. No significant differences were detected between the normotensive control subjects and the hypertensive patients with ADPKD in erythrocyte sodium-lithium countertransport activity, plasma renin activity, plasma aldosterone concentration, or atrial natriuretic factor. These results suggest that the renal renin-angiotensin system plays a central role in the alterations in renal hemodynamics and sodium management associated with the development of hypertension in ADPKD.

Attenuated renal excretory response to atrial natriuretic peptide in congestive heart failure in man

The renal and hormonal effects of atrial natriuretic peptide given as a bolus injection (2.0 μg/kg) were studied in 12 patients with congestive heart failure before and after treatment with captopril for 4 weeks and in 13 healthy control subjects. Atrial natriuretic peptide caused a rise in urinary excretion of sodium and urinary flow in the controls, whereas no increases were observed in the patients. Both proximal and distal fractional reabsorption of sodium, as evaluated by the lithium clearance technique, decreased less in the patients than in the controls. Basal plasma concentrations of atrial natriuretic peptide and cyclic guanosine monophosphate (cGMP), and the basal urinary excretion of cGMP, were elevated in the patients. The increases in both plasma and urinary cGMP after administration of atrial natriuretic peptide were blunted in heart failure. Basal glomerular filtration rate and renal plasma flow were reduced, and filtration fraction increased, in the patients. A positive correlation ( r = 0.958, P < 0.01) was found between renal plasma flow and the relative increase in urinary excretion of sodium in the patients with heart failure. Treatment with captopril did not improve the natriuretic and diuretic effect of exogenous atrial natriuretic peptide, but resulted in an increase in filtration fraction after administration of atrial natriuretic peptide not present before captopril. It is concluded that the natriuretic and diuretic effect of exogenous atrial natriuretic peptide is blunted in congestive heart failure in man due to reduced responsiveness in both proximal and distal tubules. It is suggested that preoccupation/downregulation of the receptors for atrial natriuretic peptide rather than the reninangiotensin-aldosterone system, is involved in the pathogenesis of the attenuated renal response to exogenous atrial natriuretic peptide in congestive heart failure.

Effects of endothelin on renal haemodynamics and segmental sodium handling in conscious rats

The effects of endothelin (100 and 600 pmol/kg) on renal plasma flow (RPF), glomerular filtration rate (GFR), sodium excretion (UNa V) and segmental sodium handling were investigated in conscious rats. Low-dose endothelin decreased renal plasma flow by 26% without affecting glomerular filtration rate and sodium excretion. High-dose endothelin reduced renal plasma flow, glomerular filtration rate, sodium excretion and lithium clearance by 57, 45, 38 and 52%, respectively. The fall in sodium excretion was not due to a direct effect of endothelin on tubular sodium transport since sodium excretion corrected by glomerular filtration rate and fractional proximal and distal sodium reabsorption did not change throughout the study. These results indicate that the impairment in renal perfusion is responsible for the antinatriuretic effect of endothelin in conscious rats.

Decreased Renal Clearance of Sodium in Cystic Fibrosis

In 10 patients with cystic fibrosis (CF) and 10 controls of similar age quantitative segmental handling of sodium was estimated by lithium clearance. In the CF group, there was a tendency for an increased glomerular filtration rate (GFR) and increased absolute proximal sodium reabsorption. The fractional distal sodium reabsorption was significantly (p = 0.015) increased and sodium clearance was significantly (p less than 0.01) decreased in CF.

Tubular sodium handling in cirrhotic patients with ascites as analysed by the renal lithium clearance method

The proximal and distal sodium reabsorption were calculated from lithium clearance in 21 healthy controls and 24 cirrhotic patients with ascites after 4 days under a sodium-restricted diet. The values of fractional lithium clearance were lower in patients than in controls (7.37 +/- 0.87 vs. 18.13 +/- 1.76%, P less than 0.001). Fractional proximal sodium reabsorption was increased in patients compared with controls (92.8 +/- 1.1 vs. 81.8 +/- 1.7%, P less than 0.001). No differences were found in fractional distal sodium reabsorption between controls and patients (96.9 +/- 0.8 vs. 98.6 +/- 0.1%). When patients were separated into two subgroups according to their sodium balance, it was found that fractional distal sodium reabsorption was increased in patients whose balance remained positive, compared with patients on a negative sodium balance (98.99 +/- 0.26 vs. 94.11 +/- 1.50%, P less than 0.05). In addition, the natriuretic response to a specific dose of spironolactone was higher in patients on positive sodium balance compared with patients on negative sodium balance (per cent increase in natriuresis after spironolactone 300 mg day-1: 355.24 +/- 73.98 vs. 84.21 +/- 15.8%, P less than 0.01). We conclude that proximal sodium reabsorption is increased in cirrhotics with ascites. In addition, distal sodium reabsorption is enhanced only in those patients which exhibit avid sodium retention.

Nephrotoxicity of Cyclosporin A in Patients with Newly Diagnosed Type 1 Diabetes Mellitus

Renal function was studied in 18 patients with Type 1 diabetes mellitus. All were participating in the Canadian-European randomized placebo-controlled cyclosporin trial in newly diagnosed Type 1 diabetic patients, nine being randomized to placebo, and nine to cyclosporin A. During treatment for 12 to 18 months, cyclosporin A caused significant reductions in the glomerular filtration rate (before drug withdrawal, cyclosporin 97 +/- 18 vs placebo 125 +/- 16 ml min-1 1.73-m-2, p less than 0.05), renal plasma flow (454 +/- 83 vs 536 +/- 70 ml min-1 1.73-m-2, p less than 0.05), and lithium clearance (17 +/- 3 vs 28 +/- 5 ml min-1 1.73-m-2, p less than 0.05). The fractional proximal reabsorption was increased (0.82 +/- 0.03 vs 0.78 +/- 0.03, p less than 0.05), and the fractional distal sodium reabsorption reduced (0.88 +/- 0.03 vs 0.94 +/- 0.02, p less than 0.05). These results are in accordance with the hypothesis that the nephrotoxic effect of cyclosporin A results from a preferential constriction of afferent glomerular vessels. One year after withdrawal of the drug, all variables were similar in the two groups, except for blood glucose control which was worse in the cyclosporin A treated group. When corrected for differences in blood glucose control it appeared that in three out of nine patients glomerular filtration rate had not completely returned to the reference range of the placebo group. We conclude that the nephrotoxic side-effects of cyclosporin A treatment for 1 year are reversible. There are, however, signs of minor and perhaps chronic renal injury.

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.