Solute-free Water Clearance Research Articles

Homeostatic indications for the administration of diuretics

The authors monitored the effects of the different diuretics upon the natrium and water homeostasis and acid-base balance. The aim of the study was to clarify the exact mechanisms of their action and possible ways of monitoring of their homeostatic effects. The effects of furosemide (18 patients), hydrochlorothiazide (eight patients), spironolactone (14 patients), acetazolamide (10 patients), amiloride (four patients) and manitol (eight patients) were monitored in critically ill patients using computer programme utilizing 17 routinely monitored input values and calculating creatinine clearance, tubular resorbtion excretion fractions of sodium, potassium, water and osmotically active substances, clearance of the osmotically active substances, clearance of solute free water, electrolyte clearance, electrolyte free water clearance, urine outputs of sodium, potassium and urea, urea concentration index and serum and urine anion gaps. The development of parameters typical for each diuretic was evaluated using Student's t-test comparing the values before and during the treatment with the agent.

Pathophysiology of renal fluid retention

Central to a unifying hypothesis of body fluid regulation is maintenance of arterial circulatory integrity. This may be disturbed by arterial underfilling, either from reduction in cardiac output or by peripheral arterial vasodilation. In cardiac failure (CF), cardiac output falls and the nonosmotic release of arginine vasopressin (AVP) and expression of AVP mRNA in the hypothalamus are stimulated. V2 AVP receptor antagonists correct the impaired water excretion in rats with low-output CF, increase solute free water clearance, correct the hyponatremia in congestive CF patients, and normalize urinary concentrations of the aquaporin-2 (AQP-2) water channels. In conditions associated with peripheral vasodilation, such as cirrhosis, nonosmotic release of AVP also occurs, and AQP-2 gene expression in the rat kidney is up-regulated. In cirrhosis, nitric oxide-mediated vasodilation occurs early prior to water retention. V2 antagonists reverse the latter. In normal pregnancy, plasma AVP is relatively high for the degree of hypoosmolality. Pregnant rats up-regulate AQP-2 in the renal papilla, an effect reversed by V2 receptor antagonists. This supports the hypothesis that AVP is an important mediator of renal water retention in pregnancy. In summary, AVP-mediated water retention through collecting duct AQP-2 water channels is important in both low-output CF and high-output states such as cirrhosis and pregnancy. V2 receptor antagonists reverse the water retention and down-regulate AQP-2 water channels.

Evaluation of Renal Tubular Functions in Convalescent Phase of Hemorrhagic Fever with Renal Syndrome

To evaluate renal tubular functions and to investigate the causative factors of urinary-concentrating defects in the late stage of hemorrhagic fever with renal syndrome (HFRS), 11 HFRS patients in the convalescent phase were studied and compared with 8 acute renal failure (ARF) patients in convalescence (disease controls) and 9 healthy adults preparing for kidney donation (normal controls, NC). Minimal urine osmolality induced by water loading was higher (p < 0.05) in HFRS (89.5 ± 22.1 mosm/kg) and ARF patients (84.8 ± 14.7 mosm/kg) than in NC (47.8 ± 4.6 mosm/kg), but the solute-free water clearance of HFRS patients (9.0 ± 1.3%), measured at maximal diuresis, was not different from that of ARF patients (6.7 ± 1.2%) or NC (10.5 ± 1.4%). After 12-hour water deprivation + vasopressin stimulation, HFRS had lower urine osmolality (433.7 ± 31.1 versus 850.0 ± 35.1 mosm/kg; p < 0.05), urine-to-plasma osmolality ratio (1.47 ± 0.11 versus 2.91 ± 0.11; p < 0.05), and solute-free water reabsorption (0.53 ± 0.07 versus 0.91 ± 0.12%; p < 0.05) than NC. As compared with ARF patients (1.09 ± 0.16%) or NC (1.49 ± 0.16%), HFRS patients (0.43 ± 0.20%) had lower solute-free water reabsorption measured at maximal antidiuresis induced by water deprivation + vasopressin stimulation + hypertonic saline infusion (p < 0.05). In HFRS, the plasma vasopressin level and plasma vasopressin/osmolality ratio increased from 3.9 ± 0.8 to 6.1 ± 1.1 pg/ml and from 0.013 ± 0.003 to 0.020 ± 0.004 pg/ml/mosm/kg after 12-hour water deprivation, respectively (p < 0.01). However, neither basal nor stimulated values of the plasma vasopressin level or plasma vasopressin/osmolality ratio was different among the 3 groups. HFRS patients were not different from ARF patients or NC in lithium clearance, urinary-acidifying capacity, and fractional excretions of sodium, potassium and bicarbonate. We conclude that in the convalescent phase of HFRS, the urinary-acidifying ability is not disturbed, the urinary-diluting defect is mild, and the urinary-concentrating capacity is obviously impaired. This study suggests that the most important factor contributing to the urinary-concentrating defect in HFRS is the reduced collecting duct responsiveness to vasopressin.

A novel natriuretic, hypotensive factor derived from the spleen

Previous experiments have shown that the reduction in plasma volume observed after administration of atrial natriuretic factor is abolished by splenectomy. In order to determine whether the spleen contains a factor that influences cardiorenal homeostasis, rat spleens were homogenized in phosphate-buffered saline, centrifuged, subjected to ultrafiltration (molecular weight cut-off 10,000), extracted on C 18 affinity columns and dried. After reconstitution in isotonic saline, the extract was injected I.V. into conscious rats. In response to this extract, there was a dosedependent diuresis, natriuresis, kaliuresis and chloruresis which plateaued during the second and third hours following administration. Solute-free water clearance was inversely related to urine output. Blood pressure fell significantly from 109 ± 3 mm Hg to 103 ± 3 mm Hg during the first 10 min. after injection of the extract, and tended to remain depressed thereafter. There was no accompanying increase in heart rate. We conclude that the mammalian spleen contains a natriuretic, hypotensive factor that may play a role in cardiorenal homeostasis.

Volume-homeostatic mechanisms in humans during graded water immersion.

The purpose of this experiment was to investigate whether a graded increase in cardiac distension induced by graded water immersion (WI) could be related to endocrine responses and renal sodium excretion (UNaV). On 3 separate days, nine healthy males were investigated in the upright seated position before, during, and after 3 h of WI to the midchest (CI) or to the neck (NI) or during control. Central venous pressure increased twice as much during NI as during CI. UNaV increased to the same extent during NI compared with CI, whereas urine flow rate, solute-free water clearance, and osmotic excretion increased more during the 2nd h of NI than during CI. During NI, the plasma concentration of atrial natriuretic peptide (ANP) increased twice as much as during CI. The plasma concentrations of aldosterone and norepinephrine were decreased in a similar manner during NI compared with CI. In conclusion, graded cardiac distension induced by graded WI and accompanied by a graded release of ANP was not accompanied by a graded increase in UNaV. Thus either a cardiac distension pressure of approximately one-half of that during NI is enough to induce a maximum UNaV during WI or other stimuli are important. Furthermore, aldosterone and norepinephrine are probably more important mediators of the natriuresis of WI in humans than is ANP.

The differential effects of circulating norepinephrine and neuronally released norepinephrine on sodium excretion in humans.

The renal effects of incremental infusions of norepinephrine (placebo, 0.025 mu/kg/min), 0.075 micrograms/kg/min, phenylephrine (placebo, 0.5 micrograms/kg/min, 2.5 micrograms/kg/min), and tyramine (placebo, 2 micrograms/kg/min, 15 micrograms/kg/min) were examined in three respective groups (n = 9, 8, and 8) of normotensive male subjects undergoing water diuresis. Tyramine is an indirect sympathetic agent that causes neuronal release of endogenous norepinephrine. Increases in mean arterial pressure during each high-dose infusion were comparable in all three groups. Both norepinephrine and phenylephrine caused a decrease in urinary sodium excretion and effective renal plasma flow, with no changes in glomerular filtration rate. Proximal tubular sodium reabsorption, as assessed by both lithium clearance and solute-free water clearance methods, was increased by pressor doses of norepinephrine and phenylephrine. In contrast, a similar pressor dose of tyramine was associated with a pressure natriuresis, an increase in effective renal plasma flow, and a decrease in proximal tubular sodium reabsorption. Our data indicate that, in normotensive humans, circulating catecholamines (norepinephrine and phenylephrine) have opposite effects on renal sodium handling from neuronally released norepinephrine (tyramine).

Volume-homeostatic mechanisms in humans during a 12-h posture change.

On one day six male subjects underwent an upright seated (SEAT) study, and on another day they were subjected to a head-down tilt of 3 degrees (HDT). Compared with SEAT, HDT induced prompt increases in central venous pressure (CVP) from -0.5 +/- 0.8 to 8.3 +/- 0.3 mmHg (P < 0.001) and in arterial pulse pressure of 8-18 mmHg (P < 0.001). CVP stabilized after 6 h at levels 2.4-2.8 mmHg below the peak value. Simultaneously, renal sodium excretion gradually increased over the initial 5 h of HDT and stabilized at a level approximately 125 mumol/min over that of SEAT (P < 0.001). Urine flow rate and solute free water clearance increased during the initial 2-6 h of HDT (P < 0.001) but returned to the level of SEAT thereafter. We concluded that CVP is slightly reduced over 12 h of HDT and that a clear temporal dissociation exists between renal sodium and water handling. We suggest that the combined effect of the sustained suppressions of plasma renin activity and plasma aldosterone and norepinephrine concentrations constitutes a mechanism of the increase in renal sodium excretion.

Prazosin blunts the antinatriuretic effect of circulating angiotensin II in man.

The present study examines the role of alpha 1-adrenoceptors in determining the renal haemodynamic and sodium excretory responses to a physiological dose of angiotensin II in man. The effects of a low-dose infusion of angiotensin II (1 ng/kg per min) and a non-depressor dose of prazosin (0.25 mg), alone and in combination, on urinary sodium excretion (UNaV), effective renal plasma flow (ERPF), glomerular filtration rate (GFR) and segmental tubular function were studied in eight normal male subjects. Subjects were studied undergoing maximal water diuresis. Clearances of inulin and para-aminohippurate were employed to estimate GFR and ERPF, respectively. Segmental tubular handling was assessed by both lithium clearance (CLi) and solute-free water methods. Angiotensin II decreased UNaV without altering ERPF and GFR. Angiotensin II caused a significant fall in fractional CLi, which may indicate a proximal tubular effect of angiotensin II. Angiotensin II alone also increased fractional reabsorption of sodium delivered to the distal nephron, as evaluated by both the CLi method and by estimation of solute-free water clearance. When angiotensin II was given in combination with prazosin, which on its own had no apparent effects on any renal parameters, the antinatriuretic and tubular effects of angiotensin II were significantly blunted. These findings suggest that low doses of circulating angiotensin II are able to modulate UNaV by increasing sodium reabsorption in the proximal and, to some extent, the distal nephron segment in man. The study also showed that a non-depressor dose of prazosin blunted the renal effects of angiotensin II, thereby providing tentative evidence of a renal interaction between alpha-adrenoceptors and angiotensin II in man.

Nitrendipine and Renal Tubular Function in Human Volunteers

Nine normotensive, water-loaded subjects received 10 mg oral nitrendipine, and eight subjects received placebo in a double-blind randomized manner. Urine and plasma were collected at fixed time points for 1 hour before and for 4 hours after drug administration for biochemical measurements. Glomerular filtration rate was measured by inulin clearance and effective renal blood flow was measured by para-amino hippurate clearance. Absolute sodium excretion increased by 25.9% from 0.27 +/- 0.03 mmol/min to 0.34 +/- 0.02 mmol/min (P = .02), and fractional sodium excretion increased by 32.3% from 18.9 +/- 3.0% to 25.0 +/- 1.9% (P = .03) after nitrendipine, but both were unchanged after placebo. There was no change in inulin clearance, para-amino hippurate clearance, urine volume, or fractional excretion of uric acid, which made an effect on glomerular filtration, renal blood flow, or proximal tubular function an unlikely explanation of the natriuresis. Fractional excretion of magnesium increased after both placebo and nitrendipine administration, from 5.0 +/- 0.6% to 6.8 +/- 0.7% (P = .027) and 5.7 +/- 0.8% to 8.8 +/- 1.0% (P = .006), respectively. Fractional excretion of phosphate also increased after both placebo and nitrendipine, from 9.5 +/- 2.3% to 12.9 +/- 3.9% (P = .05) and 9.7 +/- 1.7% to 14.2 +/- 1.9% (P = .002), respectively. These changes are likely to be due to the effects of the water load rather than due to a drug effect. There was no change in clearance of solute free water, which made a direct effect on the loop of Henle or cortical diluting segment unlikely.(ABSTRACT TRUNCATED AT 250 WORDS)

Haemodynamic and renal tubular effects of low doses of endothelin in anaesthetized rats.

1. Renal haemodynamic and tubular transport responses to low-dose infusions (1 and 10 ng kg-1 min-1) of endothelin were investigated in anaesthetized rats. 2. Both doses caused transient increases in mean arterial blood pressure (17 +/- 5 mmHg, P < 0.05 at 1 ng kg-1 min-1) followed by sustained hypotension (-14 +/- 5 mmHg, P < 0.05), reduced renal vascular resistance (-42%, P < 0.05) and increased renal plasma flow (46%, P < 0.05). Glomerular filtration rate was unchanged. 3. Each dose caused profound diuresis and natriuresis. At 1 ng kg-1 min-1 urine flow rate and fractional water excretion increased 5-fold and fractional sodium excretion 10-fold. Fractional potassium excretion and solute-free water clearance were unaltered. 4. End-proximal fluid delivery estimated by lithium clearance doubled (P < 0.05) and fractional proximal and distal sodium reabsorption decreased 10-20% (P < 0.05). Absolute proximal reabsorption also fell with the higher dose. 5. Hypotension and natriuresis persisted for 30 min after terminating infusions. Time-control animals showed no changes in haemodynamics or renal tubular transport. 6. It is concluded that endothelin, at low concentrations, causes renal vasodilatation with concomitant natriuresis due to reduced sodium transport in proximal and distal nephron segments.

Evidence for a Proximal and Distal Nephron Action of Atrial Natriuretic Factor in Man

The intrarenal mechanism of action of atrial natriuretic (ANF) remains uncertain. Animal work suggests that part of the natriuretic effect of ANF may be due to inhibition of proximal and distal nephron sodium reabsorption and we now present evidence for similar effects of ANF in man. Six sodium replete normal male volunteers were studied during maximal water diuresis. Lithium clearance was used to assess segmental nephron function. ANF infusion caused a significant increase in fractional lithium clearance (FELi) compared to placebo infusion. A similar change in fractional distal delivery, a conventional marker of proximal tubular outflow, also occurred during ANF infusion independently corroborating the increase in FELi. These findings suggest that ANF inhibits whole-kidney fractional proximal tubular sodium reabsorption in man. Evidence is also presented to show that ANF depresses distal nephron fractional sodium reabsorption as evaluated both by the lithium method and by estimation of solute-free water clearance.

An examination of the site and mechanism of action of torasemide in man.

Acute clearance studies were performed in normal subjects to determine the site and mechanism of action of torasemide (isopropyl-1-methyl-3 phenylamino-4 pyridil-3 sulphonyl-3-urea), a new diuretic agent, in the human kidney. The drug caused no change in glomerular filtration rate or effective renal plasma flow. Sodium excretion rose to 16% of filtered load, whereas there was a chloriuresis of 23%. During maximal water diuresis, the drug caused an increase in urine flow rate and a decrease in solute-free water clearance. Administration of the drug during hypertonic saline infusion into hydropenic subjects resulted in a marked decrease in water reabsorption from the collecting duct. Torasemide caused no change in phosphate excretion or in the percentage of filtered bicarbonate excreted, nor was urinary pH or net hydrogen ion excretion affected by the drug. The data suggest that the primary site of action of torasemide is the medullary portion of the ascending limb of the loop of Henle.

Renal responses to atrial natriuretic factor in hydrated and hydropenic dogs

Atrial natriuretic factor (ANF 101–126) was compared to the standard diuretics, furosemide and hydrochlorothiazide, and to the vasodilator, acetylcholine in hydrated and dehydrated anesthetized dogs. ANF 101–126 (20 pmole/kg/min, ira) modestly reduced solute-free water clearance in water-loaded dogs and slightly lowered free water reabsorption in dehydrated animals. This pattern of responses most closely resembled those produce by 10 mg/kg, ira of the distally-acting diuretic, hydrochlorothiazide and a natriuretic dose of acetylcholine (2.5 μg/kg/min, ira). In contrast, the loop diuretic, furosemide (1 mg/kg, ira) drastically suppressed both free water clearance and reabsorption. ANF 101–126 produced changes in free water handling which were not readily distinguishable from those induced by either hydrochlorothiazide, a distally-acting diuretic, or acetylcholine, a vasodilator.

CONTRIBUTION OF THE FETAL KIDNEY TO PRESERVATION OF FLUID VOLUME DURING HYPOVOLEMIA

Vasopressin in fetal plasma (VPp) has been shown to increase following mannitol infusion to the mother (Leake, R.D. et al, Pediatr. Res.13:841, 1979). It was suggested that this increase was related to the hyperosmolality and/or hypovolemia induced by transfer of water from fetus to mother. In order to examine the response of the fetal kidney to these changes, we studied six chronically instrumented fetal lambs 120-131 days gestation following infusion of mannitol to the mother. Mannitol infusion caused an increase in osmolality of maternal plasma from 298±3.1 to 311±2.0 mOsm/kg. In addition this treatment caused an increase in fetal VPp from 1.9 to 3.2 pg/ml and osmolality (OsMp) from 292±2.9 to 299±2.1 mOsm/kg (Mean ±S.E.). Following infusion there was also a fall in fetal urine output from 0.15±0.019 to 0.10±0.009 ml/kg min and a rise in urine osmolality from 140±8.6 to 183±13.2 mOsm/kg (p<0.01). These changes led to a significant decrease in solute free water clearance from 0.08±0.009 to 0.05±0.004 ml/kg min but not in osmolar clearance. These studies indicate that: 1) Mannitol to the mother induces a rise in fetal OSMp, 2) the rise must be due to transfer of water to the mother rather than fetal diuresis and 3) the fetal kidney contributes to the preservation of fluid volume in response to hypovolemia. Furthermore these results raise the possibility that diuretics given during pregnancy may cause dehydration in the fetus.

Dysfunction of the proximal tubule underlies maleic acid-induced type II renal tubular acidosis.

To investigate whether dysfunction of the proximal tubule underlies maleic acid-(MA) induced type II ("proximal") renal tubular acidosis (RTA II), we intravenously administered either MA or acetazolamide to eight conscious trained dogs undergoing water diuresis and examined the relationship between fractional solute-free water clearance (Ch2o/GFR), a measure of NaCl reabsorption in the post-proximal nephron, and either fractional urine flow (V/GFR), a measure of total solute rejected by the proximal tubule, or the sum of fractional excretion of Cl- and Ch2o/GFR [(Ccl + Ch2o)/GFR], a measure of proximally rejected solute that is potentially reabsorbable by the thick ascending limb. When MA or acetazolamide induced brisk bicarbonaturia at normal plasma bicarbonate concentrations: 1) V/GFR, (Ccl + Ch20)GFR, and Ch2o/GFR increased strikingly; 2) at any increment of Ch2o/GFR ws not; 3) the increments of V/GFR correlated positively with those of fractional excretion of bicarbonate (P less than 0.001); 4) during hyperchloremic acidosis, MA-induced bicarbonaturia was greatly attenuated; the increment in V/GFR was halved and approximated that in Ch20/GFR, which was unchanged; 5) when plasma bicarbonate was abruptly increased, bicarbonaturia increased strikingly and V/GFR increased further but Ch20/GFR and aminoaciduria did not. We conclude that MA induces a reduction in the net rate at which the proximal tubule reabsorbs HCO-3, Na+, and Cl-. This dysfunction underlies RTA II and evokes greatly increased reabsorption of Cl- and Na+ in the post-proximal tubule.

Factors moderating the effect of oral sulfonylureas on free water clearance.

The effects of the antidiuretic agent chlorpropamide and the diuretic agent tolazamide on solute-free water clearance (CH2O) were compared in noninsulin-dependent diabetic patients undergoing water diuresis. Hyperglycemia (fasting serum glucose above 200 mg/dl) obscured the effects of these two sulfonylureas on CH2O. Thiazide or ethacrynic acid enhancement of chlorpropamide antidiuresis was also blunted by hyperglycemia and attendant osmotic diuresis. Thus, the low incidence of symptomatic hyponatremia during chlorpropamide treatment of diabetic patients may be explained by persistent hyperglycemia in such patients.

Renal effects of bumetanide.

Upon administration of bumetanide in normal human subjects, both glomerular filtration rate and effective renal plasma flow were increased, in approximately proportional amounts. Sodium excretion rose to 16 per cent of filtered load, whereas there was a chloriuresis of 23 per cent. During maximal water diuresis, the drug caused an increase in urine flow rate associated with a rise in osmolal clearance and no change in solute-free water clearance. Intravenous injection of the drug during hypertonic saline infusion into hydropenic subjects resulted in the virtual abolition of water abstraction from the collecting duct. The drug caused a modest increase in phosphate excretion but no change in the percentage of filtered bicarbonate excreted. Furthermore, neither urinary pH nor net hydrogen ion excretion was altered by the drug. The data suggest that bumetanide has its major action in the loop of Henle but that it also inhibits sodium transport in the proximal tubule. In addition, the nature of the proximal action does not appear to be related to a carbonic anhydrase inhibitory effect. These latter observations regarding the proximal action of the drug were verified by micropuncture studies performed in the dog.

Prostaglandins in urine of foetal lambs.

ALTHOUGH prostaglandins of the E and F series have been measured in amniotic fluid from several species1–3 their principal site of synthesis remains uncertain. In man, for example, the decidua4,5 foetal membranes6,7 and myometrium8 have all been shown to synthesise prostaglandins in vitro and each may contribute to the prostaglandin composition of amniotic fluid. The foetal lung and kidneys secrete considerable volumes of fluid into the amniotic sac9,10 and hence may also contribute to the prostaglandin content of amniotic fluid. The levels of prostaglandins in foetal tracheal fluid have been shown to be much lower than those in amniotic fluid11 and it was suggested that foetal urine is a more likely source of amniotic fluid prostaglandins. The foetal kidney is capable of synthesising prostaglandins12 and there is a growing body of evidence that prostaglandins are intimately involved in renal function13–15. We have, therefore, measured the concentrations of PGE, PGF and 13, 14-dihydro-15-keto-prostaglandin F (PGFM) in foetal urine during late pregnancy in sheep and have further determined the osmolality, Na+ and K+ concentrations of foetal urine and plasma. The concentrations of prostaglandins measured in foetal urine were similar to amniotic fluid levels but significantly greater than those previously reported in plasma and tracheal fluid suggesting that the kidney is a major source of amniotic fluid prostaglandins. The excretions of prostaglandins were related to the rate of urine flow; the excretions of PGF and PGFM were correlated with osmolar and solute-free water clearances and Na+ excretion, whereas excretion of PGE was related only to the clearance of solute-free water. Prostaglandins may thus contribute substantially to renal function and volume homeostasis in foetal life.

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

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

A study of the renal handling of water in lipoid nephrosis.

Children with lipoid nephrosis were studies during clinical relapse and after complete remission. As expected, the calculated serum oncotic pressure was reduced severely from the remission value of 28.6 +/- 0.9 mm Hg to 15.4 +/- 1.1 (P less than 0.005) during relapse. Although no apparent change in plasma volume was noted using the volume of distribution of labeled human albumin, calculated plasma volume was reduced 13 +/- 8% during relapse when estimated from changes in hematocrit. After a water load, the ability to excrete water was markedly blunted during relapse. The clearance of solute-free water (CH2O) was 0.9 +/- 0.8 ml/min during relapse, compared with 3.6 +/- 0.6 ml/min during remission (P less than 0.005). In addition, there was a reduced maximal urinary concentrating ability during relapse in four of the six patients examined. Mean urine osmolality for the group during relapse was 778 +/- 82 mOsm/kgH2O and 991 +/- 71 during remission (P less than 0.05). The demonstrated alteration in nephron function during relapse of nephrotic syndrome could result from either (1) a decrease in the amount of sodium delivered to the ascending limb of the loop of Henle because of increased proximal reabsorption or (2) a change in the intrinsic characteristics for sodium reabsorption in that segment. Although this observation does not prove that proximal reabsorption is increased, it suggests a common underlying mechanism for altered nephron function in all of the major edema-forming conditions.