EDITORIAL COMMITTEE

Tomas Berl, Editor William Henrich Mark Paller Fred Silva Denver, CO Toledo, OH Minneapolis, MN Oklahoma City, OK

Nephrology Trainee Program, St. Michael’s Hospital, University of Toronto

St. Michael’s Hospital is a major teaching center of the University of Toronto located in downtown Toronto. The nephrology training program at St. Michael’s offers a broad-based clinical experience coupled with the opportunity to work in a variety of basic research and clinical investigation sethngs. The program is designed for individuals who seek to pursue careers in nephrology with a major scholarly component. The patient population includes an excellent mix of general nephrology. One of the major areas of emphasis is the application of basic principles of physiology of acid-base and electrolyte disorders to the bedside. St. Michael’s Hospital also offers in-depth exposure to general nephrology. hemodialysis. continuous ambulatory peritoneal dialysis. and kidney transplantation. with an emphasis on ambulatory care. The outpatient clinics include general nephrology. progressive renal disease (predialysis). and a multidisciplinary diabetic complication clinic. There is a very active renal consultation and teaching service.

Trainees are encouraged to spend part of their training time with a staff nephrologist in the area of fluid-electrolyte and acid-base physiology. delivery of hemodialysis care. or clinical kidney transplantation. In addition. there are opportunities to participate in laboratory projects in molecular medicine, acid-base and electrolyte physiology. and transplantation immunology. The clinical experience is complemented by a formal didactic program with structured rounds in clinical nephrology. renal physiology. molecular medicine. renal biopsy rounds. journal club, and a course (1 h/wk) designed to review all of the important areas of nephrology. followed by a weekly citywide nephrology grand rounds. which includes basic science and clinical presentations. with one visiting professor per month, under the auspices of the University of Toronto nephrology training program.

Coexistence of Central Diabetes Insipidus and Salt Wasting: The Difficulties in Diagnosis, Changes in

Natrem ia , a nd Treatment1

Sheila Laredo, Ken Yuen, Brian Sonnenberg, and Mitchell L. Halperin2

the osmole excretion rate early on revealed the co- S. Laredo. K. Yuen, B. Sonnenberg. ML. Halperin. Renal existence of central Dl and an osmotic diuresis. The Division. Department of Medicine. St. Michael’s Hospi- osmoles excreted were largely Na salts; after antidi- tal. Toronto. Ontario, Canada uretic hormone acted, this electrolyte diuresis caused (J. Am. Soc. Nephrol. 1996; 7:2527-2532) the urine flow rate to be much higher than otherwise anticipated. Interestingly, part of this saline diuresis occurred when the extracellular fluid volume was ABSTRACT contracted. The tool to explain the basis for the dys- Both central diabetes insipidus (Dl) and a high rate of natremias was a tonicity balance. Hypernatremia, excretion of sodium (Na) and chloride (Cl) contrib- which developed before treatment of central Dl, was uted to the development of polyuria and dysnatre- primarily a result of a positive balance for Na rather mia in two patients during the acute postoperative than a large negative balance for water. Moreover, period after neurosurgery. To minimize difficulties in hyponatremia that developed once antidiuretic hor- diagnosis and projections for therapy, two available mone acted was primarily a result of a negative (but not often used) clinical tools were helpful. First, balance for Na; the urine volume was large and its Na concentration was hypertonic. To prevent a further 1 Received September 27, 1995. Accepted April 10, 1996.

2 Correspondence to Dr. ML. Halperin, St. Michael’s Hospital, 38 Shuter Street, decline in the plasma Na concentration, either the Na Toronto, Ontario M5B 1A6, Canada. concentration in the urine should be decreased by 1046.6673/07 12.2527$03.OO/O provision of urea or a loop diuretic while replacing all Journal of the American Society of Nephrology Copyright © 1996 by the American Society of Nephrology unwanted water and electrolyte losses; alternatively, Journal of the American Society of Nephrology 2527 Salt- and Water-Wasting

the fluid infused should have a similar Na concentra- anterior communicating artery as well as smaller tion and volume as the urine (infuse hypertonic sa- aneurysms in the right posterior communicating and line). left ophthalmic arteries were identified on computed tomography scan. Her subarachnoid hemorrhage ex- Key Words: Cerebral salt wasting. hypernatremia. hyponatre- tended into the interhemispheric region around the mia, natriuretic factors. sodium lamina terminalis and into the carotid cisterns bilat- eralby. D erangements in the plasma sodium (Na) concen- Preoperatively, she was given dibantin (800 mg) and tration are commonly observed after surgery. Decadron (Dexamethasone; Merck-Sharpe & Dohme, especially with procedures that involve the pituitary Pointe Claire, Dorvab, Quebec, Canada; 4 mg). The gland (reviewed in Reference 1 ). Our purpose in this bleeding aneurysm was clipped, the procedure was article is to provide a rationale to understand the basis thought to be without complication. and an unevent- for these dysnatremias and the expected change in ful recovery was anticipated. During surgery, she urine composition once antidiuretic hormone (ADH) is received mannitol (50 g). Decadron ( 1 0 mg), and 3 L of given. The analysis will be to focus initially on two Ringer’s lactate. In the subsequent 10 h. balance Issues. First, by examining the urine osmolality. cal- studies were carried out. During that time, her plasma culating the osmole excretion rate, and comparing it Na concentration rose from 136 to 155 mM. She to usual values (approximately 0.5 mosmol/min), one received a total of 839 mmol of NaC1 in a volume of 7.3 can determine why the urine flow rate is high. In this L. Polyuria was evident in that her urine output was regard, it is Important to know that there is usually 7.4 L (average flow rate of 12.3 mL/min) (Figure 1). little diurnal variation in the rate of excretion of urea, Because of the very high urine flow rate, low urine the principal urine osmole (2). Second, to determine osmolality (120 mosmob/kg H20, (Na) 37 mM, (K) 13 the basis for dysnatremia and to define therapy, ex- mM), and the development of hypernatremia, a diag- ternal balances for water and solutes that affect water nosis of central DI was made. This diagnosis was movement across cell membranes were calculated. confirmed when deamino-8-D-arginine vasopressin The sobutes in the body and the urine that affect water (DDAVP. Desmopressin; Ferring, North York, Ontario, distribution across the extracellular fluid (ECF):intra- Canada; 4 j.Lg) was administered and caused a prompt cellular fluid (ICF) interface are Na and potassium (K) rise in urine osmolality from 120 to 379 mosmol/kg salts (3). We shall call this a “tonicity balance.” Be- H20, together with a fall in urine flow rate (but to only cause urea readily crosses cell membranes, as well as 8 mL/min). Over the next several hours, more DDAVP inner medullary collecting duct (IMCD) membranes was given because of the false impression that there when ADH acts (reviewed in Reference 4), urea should was resistance to its actions (high urine flow rate). not affect water movement across these membranes It is important to recognize that the total urine and it is not included in the tonicity balance. volume of 7.4 L represents the excretion of 2.5 L of The presence of a high rate of Na excretion after isotonic saline and 5 L of electrolyte-free water; this neurosurgery is a common observation (reviewed in Reference 5). If both central diabetes insipidus (DI) and a high rate of excretion of NaC1 occur simubta- 10 hr before DDAVP 24 hr after DDAVP: neousby, this can have a profound effect on the plasma Na concentration as webb as on the urine flow rate and Water: 7.3 1 Water. 13.5 1 composition. In this setting, it is more difficult to Na+K: 839 mmol Na + K: 3165 mmol interpret the urinary findings. The focus of this pre- sentation is two patients who presented with dys- natremia, pobyuria. and an acute fall in ECF volume [Na] after a recent neurosurgicab procedure. Both patients had central DI at a time when they also had a barge natriuresis. Possible explanations for these findings Water: 7.4 L Water: 14.28 1 and a strategy for treatment will be presented. Na + K: 370 mmol Na + K: 2042 mmol Osmolality: 120 mosm/L Osmolality: 379 mosm/1

Balance Na + K: + 469 mmol Balance Na + K: . 877 mmol CASES Figure 1 . Tonicity balance in Patient 1 . A tonicity balance was Patient 1 calculated in the 10 h before treatment of central DI with DDAVP. The osmole excretion rate was close to 1.5 mosmol! A 42-yr-old previously healthy female (weight, 52 kg mm. The reason the plasma (Na) rose from 136 to 155 mM I 1 14 bbl) had developed a headache that had increased was a positive balance for Na + K of 469 mmol because in severity over 3 days. Nausea and vomiting began water balance was close to neutral. Balance data are just prior to her arrival in the hospital. She was provided for the 24-h period after DDAVP was given, in which somewhat drowsy. yet was easily awakened through- the plasma Na fell from 155 to 123 mM. The fall in plasma out the period before neurosurgery. The physical ex- (Na) was almost exclusively the result of negative balance amination, including the neurological portion, did not for Na (K input was 115 mmol and K loss was 172 mmol), identify a specific local lesion. An aneurysm in the again because water balance was close to neutral.

2528 Volume 7 ‘ Number 12 . 1996 Laredo et aI

excretion occurred at a time when much less electro- cabby to 3 to 4 mosmob/min and the urine volume lyte-free water was administered (Figure 1 ). thereby increased in parallel. The urine osmobality was 379 setting the stage for the development of hypernatre- mosmol/kg H20, indicating ADH actions. Hence the mia. urine composition reflected primarily a high rate of excretion of NaCl and possibly an inner medullary Comments on Patient 1 interstitial electrolyte concentration that was lower than in healthy subjects (“non-urea” osmobality is Osmole excretion rate. One cause for the initial usually close to 600 mosmob/kg H20: reviewed in polyuria was central DI. If the osmole excretion rate Reference 6). had been calculated. another possible basis for poby- Tonicity balance. A second tonicity balance was uria would have become evident, a very high osmole needed at the end of the 14-h period, when the excretion rate ( 1 .5 mosmol/min, a value that is close patient’s plasma Na bevel was close to normal. Had to threefold higher than in healthy subjects) (2). More- this been done, the eventual large decline in her over, electrolytes constituted close to 80% rather than plasma Na concentration could have been avoided. the 40 to 50% ofthe excreted osmoles (2 x (37 + 13) = Over the 24-h period, she received 1 165 mmob NaCb + 100 mosmob/L) with a total of 120 mosmol/L. There- KC1 in 13.5 L; she excreted 2042 mmol Na + K in fore, there was also a high osmole excretion rate 14.28 L. As a result of these balance data, one would because of a high rate of excretion of NaCl. At this predict a decline of 29 mM in her plasma Na concen- point. the most likely basis for the natriuresis was the tration, close to the observed values (Figure 1). ECF volume expansion resulting from the administra- The aim of therapy should have been to prevent the tion of so much NaCl (839 mmol, Figure 1 ). Mannitol development hyponatremia. Because the patient had did not contribute to the high osmole excretion rate at both a high urine flow rate and a very high urine Na this time because electrolytes and urea accounted for concentration, tonicity balance would require intrave- all the osmobes excreted. nous therapy using hypertonic saline (same (Na) as in Tonicity balance. The cause of the hypernatremia the urine) at an infusion rate equal to the urine flow that developed over the first 10-h period is illustrated rate to avoid the lethal and severe degree of hypona- in Figure 1 . If hypernatremia was simply a result of tremia that developed. Changing her intravenous central DI, one would expect to find a negative water therapy to half-normal at a rate equal to the unmod- balance with a deficit of close to 4 L: this was not the ified urine output was a “fatal error.” case. Because the patient was virtually in water bal- It is important to recognize that the patient’s rate of ance, the basis for the hypernatremia was the 469- excretion of NaCb was high, despite a low ECF volume mmol positive balance for Na. The gain in NaC1 could at this later time period. When a bobus of isotonic explain virtually all of the observed 19-mM rise in saline was given to reexpand her low ECF volume (CVP plasma Na concentration (Figure 1 ). On the basis of was -4 cm of H20), her CVP rose to 5 cm H20. Thus these balance data, the aim of therapy should have Na excretion when her circulating volume appeared to been to create a negative balance for 469 mmob of Na be low reflects a salt-wasting state rather than simply while maintaining water balance. the response to excessive administration of saline as Course in hospital. An unfortunate choice was occurred at the earlier times. made in the selection of intravenous solution to treat the patient’s hypernatremia. She was given primarily half-isotonic saline at a rate equal to urine output Patient 2 because of the diagnosis of central DI and the mis- A previously healthy 38-yr-old Asian man (weight, taken anticipation of an electrolyte-free water deficit. 55 kg [ 1 2 1 bbl) first noted headaches and dizziness 2 Over the next 24 h, her plasma Na concentration months before admission. Dipbopia and decreased declined to 1 23 mM because the Na concentration in visual acuity were more recent complaints. A barge the fluid infused (86 mM) was so much less than that sebbar and supraselbar craniopharyngioma was found in the urine (143 mM) (Figure 1, right panel). Despite and removed surgically. Intraoperativeby, the pituitary hyponatremia, DDAVP was continued with the false stalk was preserved. but extensive peripituitary dis- impression that It was needed to treat the pobyuria section was required. (urine flow rate over this period ranged from 8 to 1 1 On the second postoperative day, central DI became mL/min; osmobabity was 380 mosmol/kg H20. and evident when the patient’s plasma Na level rose from urine Na was as high as 1 74 mM). One other point 139 to 146 mM while his urine flow rate was greater merits emphasis; there was a fall in her central venous than 6 mL/min and his urine specific gravity was very pressure (CVP) from 5 cm H20 to a nadir of -4 cm of low ( 1 .000 to 1 .007; urine osmolality was not mea- H20. The patient died. probably because of brain cell sured). In response to DDAVP, his urine flow rate swelling. declined to less than 1 mL/min, the expected re- sponse. Further Comments on Patient 1 On the third postoperative day, hyponatremia was Osmole excretion rate. By the 14th hour, the excre- present ( 1 32 mM), so DDAVP was discontinued. Nev- tion of electrolytes (‘effectlve osmoles”) rose dramati- erthebess. a water diuresis did not occur and hypona-

Journal of the American Society of Nephrology 2529 Salt- and Water-Wasting

tremia became progressively more severe; his plasma plus 20 mmol KC1/liter) by IV, a total of 680 mmol Na Na concentration fell to a nadir of 1 1 2 mM on the sixth + K (Figure 2). All ofthese electrolytes infused, plus an postoperative day, although this treatment regimen additional 520 mmol of endogenous Na + K, were was not altered (Intravenous fluids were isotonic sa- excreted. This loss of 520 mmol of Na in a patient with line with 20 mM KC1 at a rate equal to his urine flow an estimated total body water of 30 L should cause a rate; Figure 2). Of great interest, overt signs of ECF fall in plasma Na level of 17 mM (520 mmol/30 L), volume depletion developed, including postural hypo- close to the observed fall in his plasma Na (20 mM, tension (systolic BP fell more than 20 mm Hg in a more Figure 2). One consequence ofthis excessive loss of Na upright position), postural tachycardia (heart rate would be a contracted ECF volume, consistent with rose 15 beats/mm), and the jugular venous column his physical findings of low jugular venous pressure height was below the sternal angle. It is important to and postural hypotension. recognize that ADH was acting because his urine It follows from the above description that there were “non-urea” osmolality was close to 600 mosmol/L two steps to take for proper treatment of the patient’s (Figure 2). Had ADH not acted, hyponatremia would hyponatremia. First, he needed a positive balance for not have developed. Na of close to 500 to 600 mmob. Second, he should have received intravenous fluids with the same elec- Comments on Patient 2 trolyte concentration (close to 300 mM NaCl) and flow Osmole excretion rate. On Days 3 to 6, there was a rate as in his urine. This is not the type of hyponatre- high rate of Na excretion because the urine Na con- mia in which the desired effect is a negative balance for electrolyte-free water, because he was in overall centratlon was 284 mM and the urine flow rate was 2 L per day. The patient’s osmole excretion rate was water balance. When his intravenous fluid was high (0.8 mosmol/min), especially when one consid- changed to 450 mM saline given at a rate equal to his ers that his rate of excretion of urea was likely to be urine flow rate, the signs of ECF volume contraction bow because of a low filtered load of urea (plasma urea abated, his plasma Na concentration rose as expected, and he had an uneventful recovery. 2.3 mM [6.4 mg/dLl together with a setting in which the fractional excretion ofurea should be considerably DISCUSSION less than the usual 50% because of the antecedent central DI while there was no protein intake) (7). It is In this section, we shall address issues of Na and important to recognize that this very high rate of Na water balance by considering the following questions: excretion (close to 600 mmob of Na/day) occurred 1 . Why was the rate of excretion of NaCl so high in when there was a contracted ECF volume, no diuretics these patients? were given, and there was no organic osmotic diuretic 2. What determined the urine flow rate when ADH acting (no urine osmolab gap). acted? Tonicity balance. To understand why hyponatremia 3. Why was the concentration of NaCl so high in their became more severe on Days 3 to 6, it is helpful to urine? perform a tonicity balance. The patient was in external balance for water, receiving and excreting equal vol- 1 . Why Was the Rate of Excretion of NaCI So umes of water. With respect to electrolytes, he re- High in These Patients? celved 4 L of somewhat hypertonic fluid (isotonic NaC1 Both patients had a very high rate of excretion of Na as a component of their clinical picture. There are Water: 4 L several factors that could have led to this natriuresis. [Na+K]: 154+20mM Although NaCl intake before surgery could have a direct bearing on the ongoing rate of excretion of Na (8), the primary reason for the patients’ natriuresis was the ECF volume expansion induced by the large [Na] infusion of isotonic solutions to maintain blood pres- sure during surgery. Moreover, this infusion of saline was given acutely and a large volume of isotonic saline Deficit 520 mmol Na was given to a small patient. Another factor that might Water: 4 L contribute to the natriuresis is the diurnal variation in [Na+K]: 284+18mM Na excretion (9). Healthy subjects will excrete most of Figure 2. Tonicity balance in Patient 2. The balance data the Na and Cl consumed the day before, even if there provided explain why hyponatremia developed when ADH is no intake of NaC1 today (9). was acting. Water balance was achieved but the patient lost In addition to the physiologic response of a natri- more Na than was infused. In quantitativeterms, 616 mmol of uresis because of an Na load, the rate of Na excretion Na were infused and 1 136 mmol of Na were excreted in this may be augmented by the presence of an inhibitor of period. Hence there was a net deficit of 520 mmol of Na from Na reabsorption by the kidney. the so-called cerebral the body. There was virtual K balance. Treatment was then salt-wasting syndrome (reviewed in Reference 5); this instituted with a bolus of hypertonic saline (450 mM). syndrome of salt-wasting is frequently described in

2530 Volume 7 . Number 12 ‘ 1996 Laredo et al

patients with a subarachnoid hemorrhage (reviewed water in the distal nephron. The second factor is the in Reference 5). Among the factors that might operate degree of hypertonicity of the medullary interstitial are a stimulation of cardiac contraction beading to a fluid. Because urea is permeable in the terminal IMCD pressure natriuresis (9a), and/or the release of atrial (4, 14, 15), the tonicity of the inner medullary intersti- natriuretic factor (ANF) or one of its analogues. In fact, tium is a result of its electrolyte concentration. To an ANF analogue of a central nervous system origin have a high electrolyte concentration here, one must could contribute to the observed natriuresis in pa- deliver as little electrolyte-free water as possible to the tients who have the syndrome of cerebral salt-wasting IMCD when ADH has acted. This is accomplished by ( 10). The physical findings of hypotension and a low having little urea delivery to the outer medubbary

CVP associated with high rate of excretion of Na collecting duct where urea is Impermeable and retains suggest that a salt-wasting syndrome contributed to electrolyte-free water with it in the lumen. Moreover, the natriuresis in the first several days postoperatively the lower the delivery of urea to the IMCD where It in both patients. becomes permeable (ADH action [4, 14, 151). the lower will be the addition of electrolyte-free water (as an 2. What Determined the Urine Flow Rate when isosmobal urea solution) to the papillary interstitial ADH Acted? fluid. It is interesting to note that both patients had very high urine Na concentrations together with bow Building on well-accepted concepts, only particles plasma urea concentrations. restricted to one of two compartments count with respect to water distribution between these compart- ments. Hence urea does not contribute to the “effec- Therapeutic Considerations tive” osmolality or tonicity of plasma, and the total The finding of hyponatremia and the excretion of a osmolality minus the urea concentration in mM is large volume of urine with a very high concentration of used to indicate the tonicity of body fluids. Applying Na demanded immediate attention to prevent a more this same logic to the IMCD, one should only consider severe degree of hyponatremia. Three therapeutic op- impermeant particles, and not urea or total osmolality when ADH acts, because ADH leads to a high enough tions are possible. First, infuse a solution with the same concentration of Na and volume as the urine permeability for urea in the IMCD to avoid a major (hypertonic saline in this case). Second, destroy the concentration difference for urea between the lumen concentrating mechanism with a loop diuretic and of the IMCD and the corresponding interstitial fluid replace all bosses intravenously (usually Isotonic sa- ( 1 1-13). Accordingly, the “non-urea” or effective osmo- line). Because the infusion of hypertonic saline or a lality of the medublary interstitium and the number of loop diuretic can result in catastrophic errors if not impermeant particles (electrolytes) in the luminab fluid followed closely, and loop diuretics may induce a of the IMCD should dictate what the urine flow rate depletion of magnesium. a third form of treatment will be when ADH acts, using the following equation: could be considered. Because the concentration of Na Urine flow rate X “Effective” osmolality declines in the urine during an osmotic diuresis, Decaux and colleagues ( 16) recommended the admin- = Number of “effective “ osmobes excreted/time istration of urea to lower the urinary concentration of electrolytes. Because these patients had low plasma In both patients, the high flow rate after ADH was urea levels, one could consider administering 20 to given was the result in large part of the very high rate 30 g of urea. A positive response would include a rise of excretion of “non-urea osmobes (electrolytes). In in plasma urea to close to 10 mM (28 mg/dL), a larger fact, a low rate of excretion of urea would be antici- urine flow rate, and a substantial decline in the con- pated because a low rate of production of urea (e.g., centration of Na in the urine. Again. all water and consumption of a bow-protein diet) and/or the prior electrolyte losses would have to be replaced. higher fractional excretion of urea because of central DI beading to a lower BUN (plasma urea bevels were 1.9 and 2.3 mM in Patients 1 and 2, respectively). Should CONCLUDING REMARKS these patients now be obliged to excrete a maximally By calculating the osmole excretion rate, a tonicity concentrated urine over a short period of time because balance, and identifying the nature of the osmoles ADH was administered, the urine osmolality would excreted, the basis for the pobyuria and the dysnatre- reflect the maximal concentration of “effective os- mias that occur in the acute postoperative period after moles” (close to 600 mosmob/kg H20) (review in Ref- neurosurgery can be clarified. With this information, a erence 6) and a low concentration of urea. more rational plan for intravenous therapy can be deduced. The potential abnormalities included a def- 3. Why Was the Concentration of NaCI So High icit or a surplus of ADH interspersed with periods of in Their Urine? positive, neutral, or negative balances for Na. More- There are two factors to consider in order to achieve over, other types of confounding issues such as the a high concentration ofebectrolytes in the urine. First, use of mannitol and altered rates of urea excretion ADH must permit the reabsorption of electrolyte-free may further “muddy the waters.” Both patients dem-

Journal of the American Society of Nephrology 2531 Salt- and Water-Wasting

onstrated that a high rate of excretion of NaC1 can bead dilution. In: Brenner BM, Ed. Brenner and Rector’s, The to significant contraction of their ECF volume. Kidney. 5th ed. Philadelphia: WB Saunders Company; 1996:532-570. Several measures should be used to prevent poor 5. Harrlgan MR: Cerebral salt wasting: A review. Neurosur- outcomes. First, one should never assume that post- gery 1996:38:152-160. neurosurgical diuresis is a result solely of central DI 6. Halperin ML, Gowrishankar M, Mallie JP, Sonnenberg unless the osmole excretion rate is close to 0.5 H, Oh M: Urea recycling, an aid to the excretion of potassium during antidiuresis. Nephron 1996:72:507- mosmol/min (lower values are anticipated if the 511. plasma urea concentration is very low). If there Is a 7. Banklr L. Urea and the kidney. In: Brenner BM, Ed. solute diuresis, one should identify the solutes being I3renner and Rector’s, The Kidney, 5th ed. Philadelphia: WB Saunders Company; 1996:571-606. excreted. If hyponatremla develops, the urinary (Na) 8. Steele A, Gowrlshankar M, Abrahmson 5, Mazer D, should be checked, and hypotonic fluids discontinued Feldman R. Halperin ML: Postoperative hyponatremia in favor of fluids with an (Na) that Is at least as high as despite isotonic saline Infusion: A phenomenon of ‘de- salination’. Ann intern Med, 1997, in press. the urinary (Na + K); otherwise hyponatremia will 9. Moore-Ede MC, Herd JA: Renal electrolyte circadlan become more severe in degree. A barge urine volume in rhythms: Independence from feeding and activity pat- this setting should be a sign that close observation Is terns. Am J Physlol 1977;232:Fl28-F135. needed to avoid large swings in the plasma Na con- 9a. Zhang Y, Mircheff AK, Hensbey CD, et at. : Rapid redis- tribution and inhibition of renal sodium transporters centration. Moreover the cause for the polyurla may during acute pressure natriuresis. Am J Physlol 1996: change over time (e.g. , central Dl and/or a high rate of 270:F1004-F1014. excretion of NaCI), Only close observations, frequent 10. Lazzeri C. Franchi F, Porciani C, et at.: Systemic hemo- dynamics and renal function during brain natriuretic measurement of the plasma and urine electrolytes, peptide infusion in patients with essential hypertension. and an appreciation of this complex pathophysiobogy Am J Hypertens 1995:8:799-807. will prevent occasional tragedies such as occurred in 1 1 . Schmidt-Nielsen B: Urea excretion In mammals. Physlol Patient 1. Rev 1958:38:139-168. 12. Schmidt-Nielsen B. Function of the pelvis. In: Kinne RKH, Ed. Urinary Concentrating Mechanisms. Compar- REFERENCES ative Physiology. I3asel: Karger: 1990:103-140. 13. Ullrich KJ, Rumrich G, Schmidt-Nielsen B: Urea trans- 1 . Sterns RH. Clark EC, Silver SM. Clinical consequences of hyponatremla and its correction. In: Seldin DW, Gie- port in the collecting duct of rats on normal and low bisch G, Eds. Clinical Disorders of Water Metabolism. protein diet. Pflugers Arch 1967:295:147-156. New York: Raven Press; 1993:225-236. 14. Smith CI’. Lee W-S, Martial 5, Knepper MA. You G, 2. Cheema-Dhadli S. Halperin ML: Diurnal excretion of Sands JM, Hediger MA: Cloning and regulation of ex- nitrogen and sulphur after meals containing protein: pression ofthe rat kidney urea transporter (rUT2). J Clin Indications for postprandial synthesis of proteins. Can Invest 1995:96:1556-1563. J Physiol Pharmacol 1993:71:120-129. 15. You G, Smith C?, Kanai Y, Lee WS, Stelzner M, Hediger 3. Edelman IS, Leibman J, O’Meara MP, Birkenfeld LW: MA: Expression cloning and characterization of the va- Interrelations between serum sodium concentration, se- sopressin-regulated urea transporter. Nature (Lond) rum osmolarlty and total exchangeable sodium, total 1993:365:844-847. exchangeable potassium and total body water. J Clin 1 6. Decaux G, Brimioulle 5, Genette F, Mockel J: Treatment Invest l958;37: 1236-1256. of the syndrome of Inappropriate secretion of antidi- 4. Knepper MA, Rector FCJ. Urinary concentration and uretic hormone by urea. Am J Med 1980:69:99-106.

2532 Volume 7 ‘ Number 12 - 1996