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.     

Nephrotoxicity of cyclosporin A. A lithium clearance and micropuncture study in rats

Renal function was studied in rats treated with cyclosporin A (CyA). Peroral CyA 25 mg kg-1 day-1 depressed glomerular filtration rate (GFR) from 1284 +/- 429 to 500 +/- 228 microliters min-1 g-1 kidney weight (KW) (P less than 0.01). Absolute rate of proximal tubular reabsorption (APR) decreased from 1075 +/- 437 to 468 +/- 203 microliters min g KW-1 (P less than 0.01). Proximal tubular fractional reabsorption (PFR) was 67.7 and 68.5% measured with the TT/OT and fractional lithium-clearance methods, respectively. Amiloride had no effect on lithium-clearance in CyA treated rats. Acute isotonic volume expansion increased GFR and APR towards normal, while PFR remained increased. Increased sodium clearance did not normalize renal function. CyA intravenously (12.5 mg kg-1) depressed GFR and APR acutely, while PFR increased. Proximal intratubular pressures were low normal (mean 11.6 mmHg). Proximal transit times were prolonged (mean 25.2 s, P less than 0.01). Renal morphology was normal. The data are evidence against a primary tubular damage of CyA, and makes it less likely that the major lesion is located to the glomerular membrane. The results suggest that CyA nephrotoxicity mainly is due to a haemodynamic effect.     

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.     

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.     

Natriuretic effect of caffeine: assessment of segmental sodium reabsorption in humans

In order to assess the intrarenal mechanisms responsible for the natriuretic action of caffeine, the renal clearances of (51)Cr-EDTA [used as a measure of glomerular filtration rate (GFR)] and lithium (used as an index of end-proximal fluid delivery) were measured in eight healthy males before (control period) and immediately after (experimental period) a 400 mg oral dose of caffeine (given over 90 min) or placebo. In caffeine-treated subjects, the fractional excretion of sodium rose from 1.00+/-0.25% in the control period to 1.47+/-0.18% in the experimental period, while corresponding values on the placebo day were 1.04+/-0.16% and 0.70+/-0.07% respectively. GFR was unchanged following either caffeine or placebo. When compared with the placebo day, caffeine caused increases in lithium clearance (experimental period values: caffeine, 37+/-1 ml/min; placebo, 28+/-2 ml/min; P <0.001), the fractional excretion of lithium (caffeine, 34+/-1%; placebo, 26+/-2%; P <0.001) and the sodium/lithium clearance ratio (used as an index of the fraction of sodium delivered to the distal nephron that escapes reabsorption therein: caffeine, 4.4+/-0.3%; placebo, 2.8+/-0.2%; P <0.001). These results suggest that reduced fractional sodium reabsorption in both the proximal tubule and the distal nephron contributes to the acute natriuretic effect of caffeine. The data also confirm the importance of controlling caffeine intake when investigating renal function using lithium clearance.     

Atrial natriuretic peptide and renal adaptation to contralateral nephrectomy in healthy man.

Atrial natriuretic peptide (ANP), angiotensin II (AII), aldosterone (Aldo) and arginine vasopressin (AVP) in plasma were determined in 12 healthy renal transplant donors before and 5, 12, 26, 54 days after uninephrectomy (Nx) in order to study the possible role of these hormones in functional adaptation to acute reduction in renal mass. Glomerular and tubular function was studied by measurements of the clearances of 51Cr-EDTA, lithium, sodium, potassium, and albumin. ANP was 7.4 +/- 3.1 pmol l-1 (mean +/- SD) before Nx and 8.7 +/- 6.1 pmol l-1 at 5 days after Nx and remained at this level through the observation period. Aldo showed a non-significant transient fall at 5 days after Nx. AII and AVP remained normal after Nx. At 5 days after Nx glomerular filtration rate (GFR) of the remaining kidney had risen from 45 +/- 7 ml min-1 before Nx to 57 +/- 8 ml min-1 (p less than 0.01), lithium clearance had risen from 13 +/- 2 ml min-1 before Nx to 20 +/- 7 ml min-1 (p less than 0.01), and sodium and water balance was normal. To conclude, plasma ANP, AII, Aldo and AVP do not appear to be responsible for the hyperfiltration and depression of fractional proximal sodium and water reabsorption observed in recently uninephrectomized man with normal sodium and water balance.     

Effect of cisplatin on proximal convoluted and straight segments of the rat kidney

The immediate effect of cisplatin on rat proximal tubular function was investigated by two different methods, the lithium clearance method and the occlusion time-transit time method (TT-OT). Within minutes after administration of cisplatin a significant increase in lithium clearance, fractional lithium clearance (CLi/Cin) and e-TT/OT was observed (from 270 +/- 32 to 387 +/- 60 microliters/min/g kidney weight, 0.202 +/- 0.03 to 0.340 +/- 0.06 and 0.415 +/- 0.02 to 0.497 +/- 0.02, respectively). These increases indicate an increased fluid delivery from both the proximal straight segment and the late proximal convoluted tubule after cisplatin administration. Concomitantly absolute proximal reabsorption rate was significantly decreased. Intervention by saline loading (2% of body weight) did not prevent the increase in e-TT/OT, but the increase in CLi/Cin was significantly less than in the control group. This finding suggests that saline loading protects either the pars recta of the proximal tubule or the juxtamedullary nephrons. Thus, cisplatin-induced nephrotoxicity in the rat is initiated by an acute mainly proximal tubular impairment including both pars convoluta and pars recta of the proximal tubule.     

Renal lithium handling during water loading and subsequent d-DAVP-induced anti-diuresis

Assuming that lithium is exclusively reabsorbed in the proximal tubules pari passu with sodium (Na), the lithium clearance (CLi) has been advanced as an index of filtrate delivery from the proximal tubules. In order to determine whether water loads in a range commonly given during clearance studies affect CLi, we studied nine normal subjects (Na intake 150 mmol day-1) on three water loads resulting in stable urine flow rates of 2.2 +/- 0.9, 6.1 +/- 0.7 and 11.7 +/- 3.0 ml min-1, respectively. We also studied the effect of acute anti-diuresis (urine flow less than 1 ml min-1) induced by d-DAVP given i.v. at the end of all studies. Water loading up to induction of maximum water diuresis did not significantly affect absolute or fractional CLi. Sodium and chloride excretion were reduced at the highest water intake level. Administration of d-DAVP caused a 50% reduction in fractional Na excretion and a small but significant rise in fractional lithium reabsorption from 75.5 +/- 3.9 to 77.5 +/- 3.6%. We conclude that CLi is hardly affected over a wide range of water intakes and urine flow rates, despite concomitant changes in Na excretion. The finding that d-DAVP, which probably enhances Na reabsorption in the thick ascending limb of Henle's loop, also enhanced lithium reabsorption, suggests that lithium may be partly reabsorbed in this nephron segment. Thus, lithium may not be the exact, quantitative marker of Na reabsorption in the proximal tubules that it is purported to be.     

Glomerular Hemodynamics in Rats with Chronic Sodium Depletion: EFFECT OF SARALASIN

In chronic sodium depletion the glomerular filtration rate may be reduced, and alterations in proximal tubular function may contribute to the maintenance of antinatriuresis. Measurements were made by micropuncture technique in superficial nephrons of the Munich-Wistar rat of (a) the determinants of glomerular filtration rate, (b) peritubular capillary hydrostatic and oncotic pressure, and (c) proximal tubular fractional and absolute reabsorption in both a control group (group 1, n = 12) and a group of chronically sodium-depleted rats (group 2, n = 12). Single nephron filtration rate (sngfr) was 37.2+/-1.2 in group 1 and 31.6+/-1.0 nl/min/g kidney wt (P < 0.05) in group 2. Of the factors potentially responsible for the observed reduction in sngfr, there was no change in systemic oncotic pressure or the transglomerular hydrostatic pressure gradient. Sngfr was lower in group 2 because of both a reduced single nephron plasma flow (rpf) (128+/-6 vs. 112+/-5 nl/min per g kidney wt, P < 0.05) and additionally to a decrease in the glomerular permeability coefficient, L(p)A, from a minimum value of 0.105+/-0.012 in group 1 to 0.054+/-0.01 nl/s per g kidney wt per mm Hg (P < 0.01) after chronic sodium depletion. There was no difference in fractional proximal tubular reabsorption between group 1 and group 2. Absolute proximal reabsorption (APR) was reduced from 20.8+/-1.3 in group 1 to 16.3+/-0.9 nl/min per g kidney wt in group 2.The role of angiotensin II (AII) in maintaining glomerular and proximal tubular adaptations to chronic sodium depletion was assessed in subsets of groups 1 and 2 by the infusion of the AII antagonist Saralasin at a rate of 1 mug/kg per min. In group 1 rats, Saralasin had no effect on sngfr, rpf, or L(p)A, because animals remained at filtration pressure equilibrium. In group 2 rats, AII blockade was associated with an increase in sngfr from 31.6+/-1.0 to 37.1+/-1.7 nl/min per g kidney wt (P < 0.01). Rpf increased during Saralasin infusion solely as a result of a decrease in afferent arteriolar resistance from 21.7+/-2.3 to 15.2+/-2.3 10(9) dyn-s-cm(-5) (P < 0.01). Saralasin infusion did not affect the reduced L(p)A in group 2, as L(p)A remained 0.056+/-0.02 nl/s per g kidney wt per mm Hg and rats remained disequilibrated. In spite of the increase in sngfr in group 2, AII antagonism further decreased APR to 13.1+/-1.5 (P < 0.01). Distal delivery therefore, increased from a control value of 15.3+/-1.3 to 24.3+/-1.5 nl/min per g kidney wt (P < 0.01).In conclusion, both a decrease in L(p)A and a reduction in rpf were major factors mediating the decrease in glomerular filtration rate observed in chronic sodium depletion. Saralasin infusion revealed a significant effect of AII on rpf and afferent arteriolar resistance in chronic sodium depletion, but no effect of AII on either efferent arteriolar resistance or the decrease in L(p)A could be demonstrated. Saralasin had no effect in rats that were not chronically sodium depleted. In group 2 rats AII antagonism reduced APR even though sngfr increased, suggesting an influence of AII on proximal reabsorption. The marked changes observed during Saralasin infusion in the chronically sodium-depleted rat reveal important modifying effects of endogenously generated AII on both the glomerulus and proximal tubule.     

The influence of body posture on lithium clearance

To establish appropriate standard circumstances for lithium clearance measurements, a study was undertaken in 12 healthy volunteers. In each subject, the glomerular filtration rate (GFR), as estimated by [51Cr]EDTA plasma clearance, and the renal clearances of lithium, sodium and potassium were measured four times at 1-week intervals: two in the supine and one in the sitting position, and one when the subject was walking around. Glomerular filtration rate was not influenced by posture changes. On the contrary, lithium clearance, which in the supine position was 30 +/- 9 ml/min (1 SD), tended to fall in the sitting position, and fell significantly to 26 +/- 5 ml/min (p less than 0.025) in walking subjects. Absolute proximal tubular reabsorption rate of fluid correspondingly rose from 83 +/- 16 to 92 +/- 15 ml/min (p less than 0.005) and sodium clearance fell from 1.52 +/- 0.81 to 1.00 +/- 0.52 ml/min (p less than 0.05) in walking subjects. Absolute distal reabsorption of sodium decreased during walking from 4052 +/- 1219 to 3449 +/- 658 mumol/min (p less than 0.025), while fractional distal reabsorption of sodium was unchanged. Our results show a rise in proximal tubular reabsorption during moderate physical activity. Hence, when renal tubular function is studied with the lithium clearance method, standardization of posture and physical activity is important. In such studies physical activity such as walking should particularly be avoided.     

Cimetidine administration and tubular creatinine secretion in patients with compensated cirrhosis.

Cimetidine inhibits the tubular secretion of creatinine, without altering the glomerular filtration rate (GFR). During cimetidine administration the creatinine/inulin clearance ratio approaches unity in patients with renal failure. We determined the clearance of lithium (an index of fluid delivery to the distal nephron), inulin (a measure of the actual GFR) and creatinine during cimetidine administration to investigate the occurrence of tubular creatinine secretion in patients with compensated cirrhosis. A total of 12 patients with Child-Pugh A cirrhosis were studied initially. The subjects consumed a stable diet containing 100 mmol of sodium. On successive days, 9 h creatinine clearances were measured, first without and then with the oral administration of cimetidine (400 mg as a priming dose, followed by 200 mg every 3 h). During the first study day, 4 h renal lithium clearance was also calculated. A further group of five patients with fully compensated cirrhosis underwent the measurement (on successive days) of plasma inulin clearance, first without and then with the oral administration of cimetidine (same schedule of drug administration). Cimetidine administration unmasked a marked overestimation of GFR when calculated as creatinine clearance (baseline, 138+/-20 ml/min; +cimetidine, 89+/-13 ml/min; P<0.01). Consequently, during cimetidine administration the calculated lithium fractional excretion (a measure of the fraction of filtered sodium load that is delivered to the loop of Henle) rose from 21.4+/-13.2% to 32.3+/-18.9% (P<0.05), and the ratio between absolute distal tubular sodium reabsorption and filtered sodium load rose from 20.6+/-13.1% to 31.6+/-19.3% (P<0.01). Cimetidine caused no significant decrease in the actual GFR (i.e. inulin clearance) when administered to the second group of patients with compensated cirrhosis. Our data demonstrate significant tubular secretion of creatinine in patients with compensated cirrhosis and, consequently, a marked overestimation of GFR and filtered sodium load and an underestimation of the fractional distal tubular sodium reabsorption when these parameters are calculated by means of the traditional creatinine and lithium clearance computation. The true GFR (measured as inulin clearance) is unaffected by cimetidine administration.     

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.     

Nephrotoxicity of cyclosporin A in humans: effects on glomerular filtration and tubular reabsorption rates

The contention that cyclosporin A (CyA) nephrotoxicity may be due to renal afferent arteriolar constriction was inferred from rat studies showing CyA to increase renal vascular resistance, to reduce glomerular filtration rate (GFR) and delivery of tubular fluid from the end of the proximal tubule to the loop of Henle (Vprox), and to increase proximal fractional reabsorption. In order to test whether the mechanism of human CyA nephrotoxicity is similar to its rat analogue, and whether CyA treatment causes prolonged renal malfunction after drug withdrawal, renal function was investigated with clearance techniques including lithium clearance (CLi) as a measure of Vprox. The subjects were patients (n = 11) with previously normal renal function, given CyA in the treatment of ocular manifestation of extrarenal disease, or bone-marrow transplant recipients. Nine out of these eleven patients were investigated before and during CyA treatment: GFR (P less than 0.05) and Vprox (P less than 0.005) decreased while proximal fractional reabsorption increased (P less than 0.01). In six patients investigated before CyA was given, and re-examined a mean of 273 days (range 84-384 days) after CyA withdrawal, CLi was reduced (P less than 0.05) while mean GFR was not significantly lowered (0.5 greater than P greater than 0.2). In one of these six patients GFR was reduced to a subnormal value of 26 ml min-1 (1.73 m2 body surface)-1. In conclusion, human and rat CyA nephrotoxicity have the same pattern of renal functional deterioration. Cyclosporin A nephrotoxicity was evident in patients investigated a mean of 9 months after CyA withdrawal.     

The effects of cimetidine on creatinine excretion, glomerular filtration rate and tubular function in renal transplant recipients

The renal clearance of endogenous creatinine (CCr), sodium (CNa) and lithium (CLi) was determined before and after a single intravenous bolus of cimetidine in nine renal transplant recipients. The glomerular filtration rate (GFR) was measured with 125I-iothalamate clearance (CTh). The initial CCr of 65 ml/min (median) was reduced to a nadir of 46 ml/min (p less than 0.01) during the first 2 h after infusion of cimetidine. GFR remained unchanged, and thus the fractional clearance of creatinine (CCr/CTh) was reduced from 1.43 (median) to 1.03 (p less than 0.01). CNa and the fractional excretion of sodium decreased throughout the study (p less than 0.05); CLi was unchanged. In conclusion cimetidine, when measured during 1-h clearance periods, interferes with tubular creatinine secretion in the denervated kidney of transplant recipients without affecting the glomerular filtration rate or proximal tubular flow. This suggests that on-going cimetidine treatment must be taken into account when graft function is evaluated by the CCr alone.     

Effects of hyperglycaemia on kidney function, atrial natriuretic factor and plasma renin in patients with insulin-dependent diabetes mellitus.

In normoalbuminuric patients with insulin-dependent diabetes mellitus, plasma atrial natriuretic factor (ANF), cyclic GMP and active renin and the renal clearances of [99Tcm]-diethylenetriaminepentaacetic acid (DTPA) lithium and sodium were studied on a hyperglycaemia day and a euglycaemia day. Baseline euglycaemia was achieved by an overnight variable insulin infusion, which during study days was fixed at the rate necessary to maintain euglycaemia in the morning. After a baseline euglycaemic clearance period of 90 min, measurements were repeated in a new 90-min period beginning 150 min later. On the hyperglycaemia day i.v. infusion of 20% glucose was started at the end of the euglycaemic baseline period, increasing blood glucose (5.3 +/- 1.3 vs 12.1 +/- 1.2 mmol l-1, p less than 0.01). On the euglycaemia day blood glucose declined (5.1 +/- 1.0 vs 4.2 +/- 1.0 mmol l-1, p less than 0.02). Glomerular filtration rate (GFR) was unchanged by acute hyperglycaemia (127 +/- 16 vs 129 +/- 24 ml min-1, NS), but nearly normalized during maintained euglycaemia on the euglycaemia day (124 +/- 17 vs 105 +/- 16 ml min-1, p less than 0.01). When comparing the hyperglycaemic study period with the similarly timed period on the euglycaemia day, GFR was elevated by hyperglycaemia (129 +/- 24 vs 105 +/- 16 ml min-1, p less than 0.01), while the renal clearances of lithium and sodium were similar. Consequently, the calculated absolute proximal reabsorption rate of sodium and water was elevated during hyperglycaemia. Hyperglycaemia reduced the slight decline in plasma concentrations of ANF and cyclic GMP observed on the euglycaemia day. Active renin, glucagon and plasma osmolality were unchanged. In conclusion, marked changes in glomerular filtration rate are induced by changes in blood glucose concentration, but the effect is delayed and thus not directly related to renal tubular transport of glucose. Hyperglycaemia does not affect renal clearances of lithium and sodium, while proximal tubular reabsorption is markedly stimulated. These changes are not related to changes in ANF, renin, glucagon or plasma osmolality.     

Atrial natriuretic peptide increases albuminuria in type I diabetic patients: evidence for blockade of tubular protein reabsorption

BACKGROUND: It has been suggested that atrial natriuretic peptide (ANP) contributes to the glomerular hyperfiltration of diabetes mellitus. Infusion of ANP increases the urinary excretion of albumin in patients with type I diabetes mellitus (IDDM). Although the increased albuminuria is attributed to a rise in glomerular pressure, alterations in tubular protein handling might be involved. PATIENTS AND METHODS: We have studied the effects of ANP in nine microalbuminuric IDDM patients. After obtaining baseline parameters, ANP was infused over a 1-h period (bolus 0.05 microgram kg-1, infusion rate 0.01 microgram kg-1 min-1). Renal haemodynamics, sodium and water clearance and tubular protein handling were studied. RESULTS: The glomerular filtration rate (GFR) increased from 116.4 +/- 8.9 to 128.3 +/- 8.8 mL min-1 1.73 m-2, whereas the effective renal plasma flow (ERPF) decreased from 534.3 +/- 44.3 to 484.9 +/- 33.3 mL min-1 1.73 m-2 (P < 0.05). As a result, the filtration fraction was significantly higher during infusion of ANP. ANP attenuated proximal tubular sodium reabsorption. Urinary albumin excretion rose from 87.57 +/- 21.03 to 291.40 +/- 67.86 micrograms min-1 (P < 0.01). Changes in the urinary excretion of beta 2-microglobulin and free kappa light chains were more marked, the excretion of beta 2-microglobulin increasing from 0.28 +/- 0.21 to 51.87 +/- 10.51 micrograms min-1 (P < 0.01), and of free kappa-light chains from 4.73 +/- 1.74 to 46.14 +/- 6.19 micrograms min-1 (P < 0.01). CONCLUSIONS: The observed rise in albuminuria during infusion of ANP does not simply reflect a change in glomerular pressure, but might at least partly result from an attenuation of tubular protein reabsorption.     

Role for intrarenal mechanisms in the impaired salt excretion of experimental nephrotic syndrome.

A unilateral model of puromycin aminonucleoside (PAN)-induced albuminuria was produced in Munich-Wistar rats to examine the mechanisms responsible for renal salt retention. 2 wk after selective perfusion of left kidneys with PAN (n = 8 rats) or isotonic saline (control, n = 7 rats), increases in albumin excretion and decreases in sodium excretion were demonstrated in PAN-perfused but not in nonperfused kidneys of PAN-treated rats although systemic plasma protein concentration remained at control level. Total kidney glomerular filtration rate (GFR) and superficial single nephron (SN) GFR were also reduced selectively in PAN-perfused kidneys, on average by approximately 30%, due primarily to a marked decline in the glomerular capillary ultrafiltration coefficient (Kf), which was also confined to PAN-perfused kidneys. Values for absolute proximal reabsorption (APR) were also selectively depressed in PAN-perfused kidneys, in keeping with a similarly selective decline in peritubular capillary oncotic pressure measured in these kidneys, the latter also a consequence of the fall in Kf. In a separate group of seven PAN-treated rats, however, no differences were detected between PAN-perfused and nonperfused kidneys in the absolute amount of sodium reaching the early (0.77 +/- 0.09 neq/min vs. 0.74 +/- 0.08, P greater than 0.40) and late portions of superficial distal tubules (0.31 +/- 0.02) neq/min vs. 0.32 +/- 0.05, P greater than 0.50), despite the lesser filtered load of sodium in PAN-perfused kidneys. Suppressed sodium reabsorption in both proximal convoluted tubules and short loops of Henle of PAN-perfused kidneys contributed to this equalization of sodium delivery rates to the late distal tubule, as did comparable reabsorption along distal convolutions. In two additional groups of PAN-treated rats, infusion of saralasin (0.3 mg/kg per h, i.v.) led to substantial increases in total kidney GFR and SNGFR in PAN-perfused but not in nonperfused kidneys. Despite these increases in total and SNGFR, urinary sodium excretion by PAN-perfused kidneys remained at a level far below that for nonperfused kidneys, again indicating that the antinatriuresis characterizing the PAN-perfused kidney is due to alterations in sodium handling by the tubules rather than changes in GFR. These results therefore indicate (a) that reductions in Kf and depressed sodium reabsorption by proximal tubules and Henle's loop segments in this model are brought about by intrarenal rather than circulating or systemic factors, and (b) assuming that superficial nephrons are representative of the entire nephron population, renal salt retention in this model is due primarily to intrarenal factor(s) acting beyond the distal convolution.     

Lithium clearance during variations in sodium intake in man: effects of sodium restriction and amiloride

Assuming that lithium is exclusively reabsorbed in the proximal tubules in proportion to sodium and water, the lithium clearance (CLi) has been advanced as an index of filtrate delivery from the proximal tubules. However, studies in the rat and dog showed that CLi drops sharply at fractional sodium excretion rates (FENa) below 0.4% due to lithium reabsorption in the amiloride-sensitive segment of the distal nephron, which disqualified CLi as an index of distal filtrate delivery during sodium restriction in these animals. In order to investigate whether this phenomenon also occurs in man, we studied CLi in 103 normal subjects at varying sodium intakes, including marked sodium restriction. In contrast to findings in the rat and dog, no sharp drop but a gradual fall in CLi was observed at decreasing FENa values down to 0.02%. Maximum urine flow, another index of filtrate delivery from the proximal tubules, decreased proportionally, suggesting that the fall in CLi was due to enhanced proximal and not distal lithium reabsorption. Amiloride (15 mg p.o.) did not affect CLi despite unequivocal effects in the distal nephron in eight normal subjects at a mean FENa of 0.1%. In conclusion, a low FENa due to severe sodium restriction in man is not accompanied by strongly enhanced distal lithium reabsorption sensitive to amiloride. Thus, in contrast to the rat and dog, a low FENa forms no objection to use CLi as an index of sodium and filtrate delivery from the proximal tubules in humans.     

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.     

Early enhancement of fluid transport in rabbit proximal straight tubules after loss of contralateral renal excretory function.

To assess the renal functional adaptation to reduced excretory capacity, we studied whole kidney and single nephron function in anesthetized volume-replete rabbits after unilateral (left kidney) nephrectomy (UNX), ureteral obstruction (UO), or ureteroperitoneostomy (UP). At 24 h, despite the absence of measurable hypertrophy of the contralateral (right) kidney, these procedures significantly increased p-aminohippurate clearance (45-54%) and inulin clearance (CIN) (64-110%) compared with sham-operated control animals. In each group, whole kidney sodium reabsorption increased in proportion to the rise in CIN. To determine whether the intrinsic transport capacity of proximal tubule segments is altered by these maneuvers, we measured fluid volume reabsorption rate (Jv) in isolated superficial proximal straight tubule (PST) segments perfused in vitro, comparing each control tubule (obtained by biopsy of the left kidney immediately before an experimental maneuver) with a corresponding tubule segment obtained 24 h or 7 d later from the contralateral kidney. Control tubule Jv in sham-24 h animals averaged 0.48 +/- 0.04 nl/(min X mm). Jv did not change significantly at 24 h or 7 d after sham maneuvers but increased significantly at 24 h after UNX [delta Jv = 0.13 +/- 0.03 nl/(min X mm)], UO [delta Jv = 0.10 +/- 0.04 nl/(min X mm)], and UP [delta Jv = 0.13 +/- 0.04 nl/(min X mm)]. Jv remained increased by similar amounts at 7 d after UNX and UO. To evaluate whether an increase in glomerular filtration rate (GFR) might be the stimulus to this augmentation in Jv values, methylprednisolone (MP) (15 mg/kg per d) was administered daily to sham-operated animals, a maneuver which induced a 73% rise in CIN by day 5. This procedure also produced a significant increase in Jv in PST at 5 d [delta Jv = 0.16 +/- 0.05 nl/(min X mm)]. The increase in Jv evident in each group at 5 or 7 d was paralleled by an equivalent change in tubule cell volume and apparent tubule luminal surface area in UNX-7d and MP-5d; no such increments in these indices, or in apparent tubule serosal surface area were evident at 24 h in any group. Thus, a 50% reduction in renal excretory function in the rabbit provokes adjustments in renal plasma flow rate and GFR in the contralateral kidney, which are evident by 24 h. The concurrent change in Jv in PST is closely related to CIN or some associated hemodynamic process, but does not appear to require an increase in tubule cell volume or apparent surface area. The ability to detect these small in vivo changes in Jv may derive from the enhanced sensitivity of paired-kidney experiments using tubule segments obtained by renal biopsy.