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CUN. CHEM. 4017, 1220-1227 (1994) of the Clearance Concept to Hyponatremic and Hypernatremic Disorders: Application A Phenomenological Analysis Abmed Said Shoker The kidney and its response to the antidiuretic hormone (ADH) are the principal protective mechanisms necessary to maintain a normal plasma tonicity (osmolality). Hence, determination of the response of the ADH-renal axis to an abnormal plasma tonicity is an important step to understanding water homeostasis. Determination of free water clearance is the most direct clinical method to measure the ability of the kidney to reabsorb or excrete water; itcan be used as a sensitive method to study water metabolism, describing the abnormal water homeostasis in simple quantitative terms. A positive electrolyte-free water clearance denotes the excretion of excess free water. A negative electrolyte-free water clearance indicates reabsorption of excess free water. During hypertonicity, an increased concentration of ADH enhances renal reabsorptionof free water. With diminished ADH secretion and normal renal function, a substantial volume of free water is cleared in response to hypotonicstimuli. A positivefree water clearance >0.4 L/day in hypertonic conditions or a negative free water clearance during hypotonicity confirms an abnormal ADH-renal axis response. Indexing renal function/free water clearance/plasma hormone/electrolytes/osmolality Terms: Ily/antidiuretic tonic- GeneralPathophyslologyof PlasmaTonlcityDisorders Because cell membranes cannot sustain a large difference in osmotic pressure for any length of time, rapid water movement across body water compartments is of vital importance to buffer the osmotic gradient on cellular membranes (1-4). Such buffering mitigates major changes but does not normalize the plasma osmolality (tonicity). The role played by water movement in preventing major changes in plasma osmolality is similar to that of weak acids and bases acting as buffers in preventing major acid/base imbalance. Correction of plasma tomcity is the function of the antidiuretic hormone (vasopressin, ADH) (5), thirst (6), and the kidney (7, 8).’ Division of Nephrology, Department of Medicine, Royal University Hospital, University of Saskatchewan, Saskatoon, Saskatchewan S7N OXO,Canada. Fax 306-966-8021. ‘Nonstandard abbreviations: ADH, antidiuretic hormone (vasopreasin); ECF, extracellular fluid; ICF, intraceliular fluid; C, osmolal clearance; CeL, electrolyte (Na + K) clearance; C,,, free water clearance; EWC, electrolyte-free water clearance; SIADH, syndrome of inappropriate antidiuretic hormone; and TBS, total body salt. Received October 22, 1993; accepted April 11, 1994. 1220 CUN1CAL CHEMISTRY, Vol. 40, No.7, 1994 Because sodium is the main impermeable cation in the extracellular fluid (ECF), the concentration of serum sodium (and of its accompanying anion) is the main determinant of the effective plasma tomcity (9, 10). Except in conditions of increased blood glucose or the presence of exogenous impermeable substances, hyponatremia and hypernatremia are synonymous with hypo- and hypertonicity, respectively (11). Plasma tonicity is sensed by special osmoreceptors in the anterior hypothalamus (5, 12, 13). The activation set point varies from person to person (14), but in normal adults ranges between 275 and 290 mosmol/kg water. Pregnancy decreases the set point of osmoreceptor activation. Plasma sodium concentration is the physiological stimulus of the osmoreceptors. Mannitol is also an efficient stimulus, and above-normal blood glucose decreases the sensitivity of the osmoreceptors (15). Stimulation of the osmoreceptors induces secretion of ADH, which is produced by the hypothalamic neurohypophysial tract and stored in the posterior lobe of the pituitary gland. The neurotransmitters that mediate this action are unknown. The second major response to changes in plasma tonicity is the perception of thirst (16). After gain or loss of water, the addition of sodium to the ECF space or its removal will result in water moving in the direction that buffers the effect of osmotic pressure changes on cell membranes. Water movement keeps the osmotic pressure inside and outside the cell equal (except for the Donann effect). Hence, the change in osmotic pressure induced by gain or loss of water or salt is shared by the intracellular fluid (ICF) and the ECF spaces. Hypotonicity induces two main responses: (a) a decrease in thirst perception and (b) a diminished secretion of ADH, so that the production of urine is in dilute form until the water excess is excreted. Failure of either mechanism leads to hyponatremia. Hypernatremia stimulates thirst and enhances conservation of free water through increased ADH secretion. Hypertonicity is maintained in the event of failure of either response. Therefore, hypo- and hypernatremia are metabolic disorders of water, not of sodium. Thirst and the renal ability to reabsorb or secrete a substantial amount of free water are the chief effector responses necessary to maintain a stable plasma tonicity (7, 17). Measurement of these effector responses is the next logical step in determining the causes of abnormal plasma tonicity. Significance of CalculatingUrinaryOsmolaland Free Water Clearances Definitions Osmolality (9, 10) refers to the thermodynamic effect of the total number of osmotically active partides (in millimoles) dissolved in 1 kg of distilled water. It is this property that is measured by freezing point or vapor pressure methods. Plasma osmolality is determined as the total number of permeable (e.g., urea) and impermeable (e.g., Na, glucose) osmoles. Tonicity (9, 10) describes the behavior of cells in a solution. By definition, an isotonic solution is one in which the particular cells maintain a normal volume; a hypertonic solution is one in which the cells shrink to a new volume; and a hypotonic solution is one in which they swell to a new volume. Plasma tonicity (effective osmolality) is measured as the total number of only the impermeable and osmotically active solutes. Renal clearance (18), C, is defined as the volume of plasma required to supply the quantity of substance x in a given time. A positive value means that substance x is excreted more than absorbed; a negative value denotes that substance x is retained. In general, C, = (LT. V)/P, where U, is the urine concentration of x, Vis the urine flow rate, and P,, is the plasma concentration of x. Osmolal clearance (19-22), Cogm, is measured as: Coem = (1) (Uo#{248}m11)/P U,,, is the urinary osmolal concentration is the plasma osmolal concentration. Effective osrnolal clearance (electrolyte clearance), is measured as: where and P GeL = (U2(Na + K) V)/P2(Na + K) CeL, (2) This equation defines the osmolal clearance of only the effective osmoles, Na, K, and their accompanying anions. Sodium clearance is calculated as: CNa = (U2Na V)IP2N This is the measure by which the renal ability to defend the effective plasma volume is assessed. Decreased or inefficient blood volume is associated with decreased CNa. Unlike the sodium concentration in spot (untimed) urine, the clearance of sodium is corrected for the urine flow rate. In conditions of plasma hypertonicity, the expected normal renal response is to reabsorb an excess of free water. In hypotonic states, the excess free water is expected to be excreted. To directly determine whether the kidney is reabsorbing or excreting an excess volume of free water, use of the clearance concept is helpful. This approach is based on the premise that measuring free water clearance is the most direct method to determine whether free water has been abstracted from, or added to, the tubular fluid during urine concentration. Such a phenomenological analysis (8,21) may improve the un- derstanding of water homeostasis disorders. A C of 1 mllmin (1.44 ldday) means that the osmoles excreted per day occupy a theoretical plasma volume of 1.44 L. If the urine volume is 1.44 Ldday, then the excreted osmoles occupy the same urine volume as in the plasma and the urinary water concentration is similar to that of plasma water, i.e., no free water is added to or deleted from the final urine. Hence, the free water clearance (C,0), can be calculated as the difference between urine flow rate and Cm: CH20 = V - Cosm (4) Unlike urine osmolality, the calculation of free water clearance is corrected by the urinary excretion of osmoles. When C,,m >V, more free water has been absorbed than secreted by the renal tubules-a negative clearance of free water. A positive clearance of free water is predicted when V >Cm, i.e., there is a net excretion of free water. From Eqs. 1 and 4, a relatively increased urinary to plasma noneffective omolal concentration should increase Cm and decrease C,0. Because plasma tonicity is determined only by the concentration of the effective osmoles (impermeable osmoles, e.g., plasma electrolytes), a more accurate treatment of the free water deficit or surplus should exdude the noneffective osmolal (permeable osmoles that do not alter tonicity, e.g., urea and ainmonium salts) clearance from the above calculations. Electrolyte-free water clearance (EWC) (23, 24) is defined as the volume of plasma required to supply the quantity of the free water present in a given time. EWC can be measured as the urine flow rate minus the effective osmolal (electrolyte) clearance (Cej), i.e., the clearance of Na and K and their accompanying anions. Thus EWC=V- V U2(Na + K) (5) P2(Na + K) In the presence of effective osmoles in the urine other than Na and K (e.g., glucose and mannitol), their clearances also should be incorporated in the equation: EWC = - V U[2(Na + P[2(Na K) + other effective osmoles] + K) + other effective oemolee} (6) Although the relation between and EWC has not been rigorously tested, EWC is considered a more accurate method to measure free water clearance. Increased urinary urea, as in catabolic states, increases Cosm. Hence at any given urine flow rate, C,0 would underestimate free water clearance compared with that calculated via EWC. Also, in sodium-retaining states, CH2O may underestimate the actual free water clearance while overestimating the free excreted water in the syndrome of inappropriate ADH (SIADH) (22). Similarly, during chronic metabolic acidosis, the urinary concentration of NH can exceed 150 mmol/L. The increased noneffective osmolal clearance makes C, CLINICAL CHEMISTRY, Vol. 40, No. 7, 1994 1221 difficult to interpret. EWC excludes the of the ineffective osmoles on the measurement of free water clearance. A negative EWC indicates that during urine concentration more free water has been abstracted from the tubular fluid than excreted. A positive value denotes a net removal of free water from the plasma. To maintain a stable plasma osmolality, the kidney ordinarily modifies the urine osmolal and water excretion to match the fluid gain. measurement spurious effect Reference intervals During a pretranspiantation workup, 18 healthy adults, potential kidney transplant donors, were studied. All persons consented to participate in the study, and the protocol followed the ethical standards of this institution. The ages of the individuals varied from 19 to 54 years (mean ± SD, 33 ± 10.56); 12 were men, and none was taking any medications. All had normal renal inquiry showed that they were on an North American diet. Their 24-h urine proffle ranges (and mean ± SD) were: volume, 0.86-2.65 L (1.5 ± 0.55); sodium excretion, 88-357 mmol (138.5 ± function. average Dietary 52.99); potassium excretion, 30-150 mmol (65.28 ± 22.07); urea excretion, 239-950 mmol (419 ± 169.98); osmolality, 229-985.5 mosmol (609 ± 266); and creatinine, 10-24.6 mmol (14.62 ± 3.33). Table 1 illustrates the calculated water and osmolal clearances. Similar values are obtained from the literature (25-27). These values are obtained only during normal plasma tonicity and volume. Because clinically many patients with abnormal plasma tonicity may also have volume depletion, it was necessary to measure the minimum free water clearance after short-term fasting. Ten healthy adults participated in this part of the study, all of whom gave consent, which also followed the ethical standards of this institution. Their ages varied from 19 to 42 years (29 ± 11.2). All were nonsmokers and not taking any medications. All had normal renal function. All had been on an average North American diet. They then fasted for 16 h, during which time they ingested no fluids. They collected their urine during the last 2 h of fasting, from which the mean values (± SD) of the urinary electrolytes and osmolality were extrapolated: urine volume, 0.68 L (± 0.1); sodium, 68.2 mmol (± 6.7); Table 1. Urinary clearancemeasurements(24 h) from 18 normal adults. Clearance, Llday saranas Rang. 3 0.57 0.62 -7.08 -1.1 CNa EWC#{176} Calculated b to 8.74 to 2.9 to 2.24 to -1.6 to +0.86 from Eq. 4. Calculated from Eq. 5. 1222 CUNICALCHEMISTRY,Vol.40, No. 7, 1994 Mean * SD 5.69 ± 1.48 1.51 ±0.50 1.12 ± 0.38 -4.25 ± 1.48 -0.02 ± 0.51 potassium, 55.9 mmol (± 9.3); and osmolality, 914.1 mosmolJkg water (± 89.3). At the same time, their serum sodium had risen from a prefasting baseline of 137 mmolJL (± 1.16) to 140.3 mmolIL (± 0.95) (P <0.05, by Wilcoxon’s unranked t-test). Serum potassium was 3.9 mmol/L (± 0.6) at baseline, 3.79 mmolIL (± 0.2) at the end of fasting (not significantly different). Serum osmolality increased from 285.4 (± 1.7) to 291 mosmol/kg water (± 2.05) after fasting (P <0.05). Mean weight loss was 1.4 kg (± 0.6). The calculated C0 was -2.88 L/day (± 4.61), EWC was 0.035 L/day (± 0.11), GeL was 0.58 L/day (± 0.08), and Cosm was 2.12 L/day (± 0.36). Both the CH2O and EWC were not significantly different from clearances measured at ad libitum conditions of fluid and food intake. Although ADH secretion increased as expected from the significant change in plasma tomcity and sodium concentration, the free water clearances and water volume reabsorbed by the kidney were not much different from measurements under normal conditions. This finding could be explained by the relative increase in noneffective osmolal secretion (urea) under conditions of fluid deprivation. A further extension of these observations is patients with substantial volume depletion and intact renal concentrating ability. These patients produce significantly concentrated urine while conserving sodium to protect blood volume. Under such conditions, the calculated EWC is slightly positive. To ifiustrate, let us consider a patient with significant hypovolemia due to nonrenal fluid loss. A classical urine profile may include sodium 20 mmol/L, potassium 70 mmolIL, urine osmolality 800 mosmol/L, and urine volume 0.4 L/day. Because the urine electrolytes and volume are usually significantly decreased, the calculated EWC is expected from Eqs. 2 and 5 to be <0.4 L/day. These observations suggest that short-term fasting and mild volume depletion per se do not induce significant change in EWC, and that significant volume depletion is associated with a slightly positive EWC in spite of increased ADH secretion. The renal response to the homeostasis mechanisms recruited to protect blood volume and to remove the waste products through the kidney takes precedent over the renal ability to reabsorb more free water as measured by EWC. There is an obligatory volume of free water that must be secreted with the waste product, mainly urea. Note that during hypotonicity, the renal ability to excrete free water increases significantly. Because >20 L is delivered to the distal renal segment for further dilution to 50 mosmol/kg water or for concentration to 1200 mosmol/kg water (8, 28-30), the calculated EWC can vary significantly. An increased EWC (20 L/day) attests to the renal ability to defend the body against hypotonic disorders. During hypertonicity, EWC is normally <0.4 llday. In conditions of hypovolemia or ineffective blood volume, urine volume is usually decreased to <1 L/day and Na concentration to <10 mmol/L (31, 32). With plasma Na 100 mmol/L, applying Eq. 3 gives the expected CNa of 0.1 L/day. Previous attempts to describe body water homeostasis in quantitative the clearance reasons: axis response, hyponatremia is associated with EWC of >10 L/day and a positive C0. Under such conditions, an EWC of <0.5 L/day signifies abnormal ADH secretion or responsiveness, abnormal renal diluting mechanisms, or both. Further determination of TBS as determined by the sodium clearance can define the pathophysiological abnormality. During hypertonicity, EWC is expected to be <0.4 L/day. Either EWC >0.4 L/day or a positive CH2O indicates an abnormal ADHrenal axis response. Determination of the sodium clearance can help categorize the blood volume state, which can directly determine the appropriateness of the ADHkidney response to plasma tonicity disorders. In particular, CNa is the variable by which the renal response to blood volume changes is measured; unlike spot urine Na concentration, CNa calculation eliminates urine volume as a variable. In the presence of decreased TBS content, as determined by the bedside clinical examination of the intravascular volume, or diminished effective blood volume, an increased CNa (>0.2 L/day) confirms a renal source of sodium wasting. Note, however, that irrespective of plasma tonicity values, hypovolemic conditions are associated with a concentrated small volume of urine. The renal capacity to respond to ADH is restricted because of the decreased delivery of fluid to the distal tubules and the requirement to remove the noneffective osmoles. Thus, as illustrated in the above example, hypovolemic patients with hype- or hypernatremia will have a slightly positive EWC (<0.4 L/day). A slightly positive EWC is the result of the integrated renal response to changes in blood volume and tonicity and the requirement to remove waste products. Urine osmolality is ordinarily expected to be more than twice that of plasma in hypovolemic conditions. From Eqs. 1 terms have been few. As discussed here, concept can be useful for the following 1) It determines the net balance of all effector elements that affect water homeostasis. 2) It can quickly and accurately determine the ADHrenal axis response to an abnormal plasma tonicity: A positive EWC reflects a net water excretion; a negative EWC indicates a net free water gain by the kidney. 3) During plasma hypotonicity the expected normal increase in the EWC can reach +20 L/day, whereas during hypertonicity EWC is normally <0.4 L/day. The measurement of free water clearance, therefore, gains more discriminatory ability to determine the ADH-renal axis response in conditions of abnormal plasma tonicity than under normal plasma tonicity. 4) Describing the body water quantitatively promotes better understanding of the mechanisms involved. 5) In some difficult cases, where multiple effector elements are in play, phenomenological description of the existing water balance can have diagnostic value (see cases 4 and 5 below). 6) The clearance concept can help explicate the principles involved in correcting plasma tonicity disorders. Suggested Phenomenological Approach to Diagnosing Disorders of Plasma Tonicity Tables 2 and 3 ifiustrate a phenomenological approach to water homeostasis disorders. After determining the ADH-renal axis response, the clinical assessment of total body salt (TBS) and the calculation of CNa or spot urinary sodium, as the currently used method, would help categorize the etiology of an abnormal plasma tonicity. In the presence of intact ADH-renal Table 2. Phenomenoiogical approach to hypotonicity: check EWC; then assess TBS and measure CN$(L/day)EWC, L/day> 10 L/day = normal ADH-renal axis response I I free water intake, e.g., psychogenic polydipsia; <10->0.5 = Impaired ADH-renal axis response; <0.5 = abnormal ADH-renal axis response. - TBS TBS normal, normal Inappropriate t ADH hypothyroidism, e.g., drugs, hypoadrenalism f C,, (O.2) Hypovolemia due to renal salt losses ADH tTBS C,(<O.1) Hypovolemia due to extrarenal salt losses -. I ADH t C,(>O.2) Retention of H20 > Na, e.g., renal disease (<O.1) Ineffective plasma volume I ADH, liver disease, CHF, nephrotic syndrome CHF, chronicheartfailure. Table 3. Phenomenoiogical approach to hypertonicity: check EWC; then check TBS and measure C,,1,,(L/day). TBS TBA normal, C,,, normal C (O.1) EWC <0.4 1./day = normal ADH-renal axis response Nonrenal fluid losses partially (Hypovolemia - I ADH) corrected with salt, e.g., I I Extrarenal hypotonic insensible losses fluid losses Essential hypematremia EWC >0.4 1./day = abnormal ADH-renal axis response Diabetes insipidus (pure water diuresis) t C,.(>O.2) C TBS, (O.2) Osmotic diuresis (pure solute diuresis) Renal losses of H20 > Na (mixed water and solute diuresis), e.g., renal diseases (Hypervolemia -e ADH) e.g., hyperaldosteronism: Cushing syndrome, bicarbonate and hypertonic salt infusion CLINICAL CHEMISTRY, Vol. 40, No. 7, 1994 1223 and 4, the absolute value of C0 that of the urine conditions. volume ordinarily exceeds in hypovolemic and is negative Examples To clarify the usefulness of the clearance concept, I present a few ifiustrative examples. For simplicity, all measurements are taken per 24 h; they can, of course, be calculated per minute. Case 1. Patients with polyuria secondary to chronic interstitial nephritis cannot dilute or concentrate their urine efficiently. A man with this disease who had pneumonia and was unable to drink >1 L daily developed volume depletion. His serum osmolality was 320 mosmol/kg water, his serum sodium was 155 mmol/L, potassium 3.5 mmol/L, and urea 24 mmolJL. At the same time, he maintained a urine volume of 3 L/day, urine osmolality 300 mosmollkg water, urine sodium 45 mmol/L, potassium 25 mmol/L, and urea 140 mmol/L. Why did he develop hypernatremia? Calculating his C (Eq. 1) gave 2.81 L/day; his C0 (Eq. 4) was +0.19 L/day; and, from Eq. 5, his EWC was 3 [3(45 + 25)/(155 + 3.5)] = +1.68 Li/day. Hypovolemia and hypertonicity are potent stimuli for ADH secretion. Consequently, a normal renal response would have been associated with a negative free water clearance. Because of the renal disease, however, he could not conserve free water in the presence of hypertonicity. He also lost a larger amount of hypotonic fluid - than under normal conditions (the obligatory losses) due to the fever. This explains why he developed hypernaBecause of the hypovolemia, the expected CNa should have been 0.1 L/day. The relatively increased CNa (from Eq. 3), 0.87 L/day, identifles a renal saltlosing state. This condition could have been avoided if a similar amount of free water and salt, equal to that lost by the kidney and the obligatory losses, was given. Notice that his net free water secretion is underestimated if the urea clearance is not deleted from calculating the tremia. effective osmolal clearance. Case 2. Recently, a patient with a known lung cancer presented to the emergency room feeling unwell. Clinically, he was euvolemic. A repeated blood testing showed sodium at 113 mmol/L, potassium 4 mmol/L, osmolality 235 mosmol/kg water, and creatinine 70 mo1/L. The urine indices were sodium 85 mmol/L, potassium 80 mmol/L, osmolality 750 mosmol/kg water, and volume 1.2 llday. His thyroid and adrenal functions have been normal. What was the cause of his hypona- tremia? If the renal response to hyponatremia was intact, he should have had a markedly positive free water clearance because of the significantly inhibited ADH secretion induced by the hypotomcity. The C0 was -2.63 I.Iday (Eq. 4). The calculated EWC was -0.49 Ilday (Eq. 5). This means that the kidney retained excess free water, which eventually led to the hyponatremia. Instead of secreting the excess water, as a normal response to hyponatremia, a net free water was reabsorbed by the kidney. The Cc,sm of 3.83 L/day and CNa of 0.9 L/day were 1224 CLINICAL CHEMISTRY, Vol. 40, No. 7, 1994 normal ranges. They reflect a normal within tent and the renal response TBS convolume. In this to dilute the urine to plasma hyponatremic case, the inability (EWC is negative), in the presence of euvolemia and normal renal, adrenal, and thyroid functions, is diagnostic of inappropriately high concentrations of ADH (SIADH, due to the carcinoma in this case). Under the ADH, water has been reabsorbed efficiently by the distal tubules, leading to a concentrated urine. Notice that, in this example, the free water clearance as estimated by CH2O overestimated the free water absorption, because urea was eliminated from the EWC but not from the C0 calculation. Case 3. An opposite example is a patient with partial diabetes insipidus, who ordinarily had a serum sodium effect of increased of 135 mmol/L, potassium 4 mmol/L, and osmolality 285 mosmol/kg water. His usual urine profile showed sodium 40 mmo]/L, potassium 20 mmol/L, osmolality 100 water, and urine 7 L/day. Because of a recent he had been unable to drink enough. In the emergency room he was euvolemic. Laboratory results showed the following serum proffle: sodium 155 mmol/L, potassium 3 mmol/L, and osmolality 325 mosmol/kg water; urine values were: sodium 40 mmol/L, potassium 20 mmol/L, volume 5 L/day, and osmolality 200 mosmollkg water. Why did he develop hypernatremia? The calculated C of 3.07 Ilday and CN of 1.3 ldday were within normal limits. it is obvious that the normovolemic hypernatremia was due to the loss of free water. His baseline CH2O was 4.54 and the EWC was 4 L/day. During his sickness, the EWC was 3.1 Llday. Because of the relative lack of ADH, this person has been clearing excess free water that is present in 3.1 L of plasma daily. The free water intake was not enough to compensate for his excessive free water losses during his sickness. In a euvolemic hypernatremic patient, a positive EWC is diagnostic of diabetes insipidus. Under these circumstances, he should have been given a simil’ir amount of free water to prevent the development of hypertonicity and hypernatremia. While he was sick, the C0 (+ 1.93 ldday) underestimated the free water losses by 1.1 I.Iday. The next three examples illustrate that measurement of EWC is a more accurate method than CH2O to determine the renal ability to excrete or conserve water because EWC excludes the spurious effect of the noneffective osmolal clearance from the equations. Case 4. A middle-aged man with recently diagnosed lymphoma was started on chemotherapy, including cymosmol/kg influenza, clophosphamide. A few days later, he developed pneumonia and felt unwell, with intermittent nausea. He was treated with isotonic saline, 100 mLlh, for 3 days. His serum creatinine had been normal. Because of a recent increase in urine output, his intravenous infusion was increased to 250 niL/h, and a nephrological assessment was requested. On examination he was euvolemic, and his oral intake was adequate. His serum profile then showed: sodium 131 mmol/L, potassium 4 mmol/L, urea 4 mmol/L, creatinine 70 molJL, and osmolality 270 mosmol/kg water. His urine profile showed: sodium 150 mmolfL, potassium 30 mmol/L, osmolality 370 mosmol/kg water, and volume 6 L/day. What causes polyuria and hyponatremia? Urine volume consists of two components: free and isosmotic water. An increase in either component can cause polyuria, i.e., water and (or) solute diuresis. The current approach to polyuria is illustrated elsewhere (19,26,33,34). If one applies the clearance concept from reference values mentioned in Table 1, an increased EWC above 1 L/day suggests pure water diuresis. Polyuria due to sodium-diuresis is associated with CNa> 2.5 L/day. In case 4, the polyuria was caused by the increased sodium clearance as measured by the increased daily sodium excretion (900 mmol) and CNa of 6.87 L/day. He did not have diabetic insipidus because his EWC was 2 L/day. The negative free water clearance indicates that more free water was reabsorbed than excreted. This explains the hyponatremia, which was due to an underlying high concentration of A1)H caused by stress (35), nausea (36), and cyclophosphaniide (37). Severe hyponatremia did not occur because the free water absorbed by the kidney was not much larger than the nonrenal obligatory losses. This was a case of mixed solute diuresis and an inappropriate high concentration of ADH. Only calculating the water and solute clearances could easily and precisely describe the hyponatremia and polyuria in this case. Case 5. A 40-year-old man with known chronic alcoho! liver disease was admitted to the intensive care unit because of intracerebral bleeding. His course was complicated with upper gastrointestinal bleeding and further acute deterioration in his liver functions. A SwanGanz catheter was inserted to manage his fluid therapy. He had been on half-isotonic saline (NaC1 4.25 g/L) at 50 mLfh. His electrolytes had been normal with a serum creatinine of 100 imoWL. His urine output was stable at 0.5-0.8 L/day. Over the last 2 days his urine output increased to 2-3 L a day, and his serum sodium increased to 155 mmol/day. The nephrology service was asked to assess the cause of hypernatremia and polyuria. On examination, he was hemodynamically stable with a blood pressure of 100/50 mmHg. He had +4 lower limb edema and ascites. His right atrial pressure was 10 mmHg, and his wedge pressure was 13 mmHg. His most recent blood tests showed a serum sodium of 155 mmol/L, potassium 4 mmol/L, bicarbonate 26 mmol/L, chloride 116 mmol/L, glucose 8 mmoJ/L, urea nitrogen 40 mmol/L, creatinine 110 janol/L, and osmolality 360 mosmol/kg water. His concurrent urine profile showed sodium 5 mmol/L and potassium 35 mmoIjL, and it was negative for sugars or ketones; urea was 500 mmol/L, osmolality 600 mosmol/L, and 24-h urine volume was 3 L. Hypertonicity stimulates the secretion of ADH. Consequently, if the ADH-renal axis response is intact, the EWC is expected to be less than 0.4 L/day. If so, hypernatremia in that condition could be secondary to the nonrenal hypotonic fluid losses. This patient, however, had an EWC of + 2.25 L/day, which confirms an inappropriate renal free water loss. His sodium clearance was 0.096 Ldday, which signifies an enhanced sodiumconserving state, most likely due to the ineffective blood volume (17, 38). Most of the urine osmoles were due to the nonelectrolyte urea component (1500 mmollday). This case constituted an instance of water-osmotic di- uresis associated with an increased sodium conserving state. The water-solute diuresis explains the relatively increased urine volume. The increased noneffective osmolal clearance masked the diabetes insipidus. If he did not have a significantly decreased effective blood volume, his urine volume would have been larger and less concentrated. Clearly, applying the clearance concept, the presence of diabetes insipidus can be easily determined in the presence of relatively hypertonic urine. Case 6. A 35-year-old woman was admitted to the hospital because of diabetes ketoacidosis. She had a 25-year history of juvenile-onset diabetes mellitus for which she was taking insulin. During the 2 weeks prior to admission, she had a flu-like syndrome and was unable to eat her meals; for 3 days she developed nausea and vomiting. In the 2 days before admission, she had progressive weakness and felt extremely unwell, and stopped taking insulin for 24 h. On admission she was found volume-depleted. Her respiratory rate was 20/ mm, pulse rate 110/mm, and blood pressure 100/50 mmllg. The remainder of the clinical examination was otherwise unremarkable. Her serum profile showed sodium of 120 mmoJIL, potassium 3 mmol/L, chloride 80 mmol/L, bicarbonate 12 mmol/L, blood sugar 40 mmol/L, creatinine 130 mol/L, and urea nitrogen 17 mmolJL. Arterial blood pH was 7.2 and plasma osmolality, 315 mosmollkg body water. Her first 24-h urine proffle showed a volume of 2 L, osmolality 600 mosmollkg water, sodium 70 mmol/L, potassium 30 mmoL’L, urea nitrogen 300 mmol/L, and sugar 15 mmolIL. Why did she develop hyponatremia? Glucose requires insulin to cross most cellular membranes. In conditions of lack of insulin, the increased blood sugar concentration exerts an osmotic effect, causing a shift of water from the intracellular compartment to the extracellular fluid space (9). The shifted water dilutes the solutes present in the extracellular space, including sodium. For each 1 mmol increase in blood glucose above the normal concentration, serum sodium decreases by 0.3 mmolJL (20). In this case, the markedly increased blood sugar above the normal range (about 35 mmol) is expected to dilute serum sodium by 0.3 x 35 = 10.5 mmol. Strictly speaking, correction of hyperglycemia in this case would be expected to increase the serum sodium concentration from 120 to 130.5 mmol/L. The calculated C0 was -1.81 L/day, which represents the clearances of all effective (Na, K, and their associated anions; Cl and ketone bodies; and glucose) and noneffective osmoles. Because plasma glucose exerts an osmotic pressure on cellular membrane, in conditions of hyperglycemia the renal clearance of glucose (C) must be added to the electrolyte clearance in order to measure the “effective” osmolal clearance. Urine ketone anions are present as salts of sodium. CLINICAL CHEMISTRY, Vol. 40, No. 7, 1994 1225 Therefore, their effective osmolal clearance is incorporated in the electrolyte clearance. From Eq. 6, the free water clearance can be rewritten as EWC = V (C0L + In this case, the renal glucose clearance was (15 x 2)/40 = 0.75 14/day. CeL was 1.63. The net renal clearance of osmoles that can affect plasma tonicity in this case was CaL + Cgiucoe = 1.63 + 0.75 = 2.38 Lfday. Hence, EWC = 2 2.38/day = -0.38 L/day. The negative free water clearance explained the hyponatremia. It was induced by the increased ADH secretion by volume depletion, nausea, and vomiting. This case illustrates the importance of adding the renal clearances of other effective osmoles to that of sodium and potassium when one is measuring the free water clearance. Osmolites such as methanol or ethanol permeate cellular membranes easily. They do not change plasma tonicity, which is affected only by the impermeable osmoles (9). Therefore, unlike glucose, they do not directly induce changes in plasma sodium concentration. Because plasma osmolality is measured by the number of the total osmoles present, these alcohols of low molecular weight can substantially increase plasma osmolality as measured in the laboratory. Hence, the osmolal gap, as measured from the equation: osmolal gap measured plasma osmolality calculated plasma osmolality [2 x serum sodium concentration + glucose (in mmol/L) + urea (in mmol/L)], is increased. When one measures the free water clearance, the renal clearances of these alcohols and their metabolites should be treated as noneffective osmoles such as urea. Measurements of the osmolal and free water clearances are of particular importance in understanding management of hyponatremia and hypernatremic disorders. As illustrated in Table 4, volume-depleted patients develop significantly diminished effective (Na) osmolal clearance. Hence, they will be able to retain the solutes (e.g., NaC1) administered. Correction of plasma tonicity in these cases is much easier than in patients with SIADH or diabetes insipidus. In hyponatremic conditions due to SIADH, the urinary effective osmolal clearance is normal, i.e., relatively higher compared to - - - Table 4. ClassIcal urine profile In prerenal azotemla due to nonrenal fluid losses, SIADH, dIabetes Inelpidus, and sodIum-Induced dluresis (e.g., salt-losIng nephropathy). Urine msasuremnt Volume Urine sodiumb Urine osmolalit? Prerenal azotsmla SIADH ‘I, ft tc fd f fd J, Je N C.L EWC a Diabetes inelpidus N ft Salt diureals ft ft ft t N With hypo-, normo-or hypematremia. “Spot” (untimed) urinespecimens. C Na concentration vanes becauseof differenturinevolumes;however, total Na secretionis similar to that ingested as long as the patientis euvolemic. d f osmolality from In urine volume. osmolalityfrom I In urine volume. N, normal. 1228 CLINICAL CHEMISTRY, Vol. 40, No. 7, 1994 patients. Free water clearance in hyponatremic patients is inappropriately negative. Correction of plasma tonicity by the infusion of isotonic saline is mitigated by the relatively increased salt clearance and negative free water clearance. This explains why, in these cases, it is important to administer solutions with higher osmolality than the urine. Administration of furosemide may be necessary to enhance free water and decrease salt clearances (8). Patients with diabetes insipidus have a significantly positive free water clearance. To maintain normal plasma tonicity, they are required to drink a similar volume of free water to match their free water losses. An important point to observe, as ifiustrated in cases 2 and 3, is that the osmolal and sodium clearances are indicators of the effective blood volume and not plasma tonicity. Assuming a normal renal response, as long as the effective blood volume is normal, urine sodium reflects the oral intake (31, 32). In a hypo- or hypernatremic patient, with a normal effective blood volume, the volume excreted is similar to the volume ingested. Protection of blood volume overrides plasma tonicity control. In patients with volume depletion or diminished effective blood volume, the kidney is expected to concentrate the urine because of an increased ADH concentration (38) and to conserve sodium (<10 mmol/L) because of increased aldosterone secretion and recruitment of the other renal sodium-conserving mechanisms (39-41). CNa is significantly decreased, and EWC is expected to be less than 0.4 L/day. These patients conserve both sodium (to protect their intravascular volume) and water and excrete the other waste solutes in a smaller urine volume. That is why, in conditions associated with ineffective blood volume, such as congestive heart failure, sodium retention results in edema. It is the retained excess water more than sodium that leads to hyponatremia. volume-depleted Conclusion I have tried to ifiustrate the usefulness of calculating the free water and osmolal clearances in the analysis of hype- and hypernatremic disorders. If one considers the multiplicity of regulatory mechanisms that control water homeostasis, an initial description of the final net effector response in quantitative terms would help to understand the mechanisms involved. Because free water clearance is the most direct clinical method to determine the renal ability to conserve or excrete free water, the ADH-renal axis response to abnormal plasma tonicity can be easily determined by using the clearance concept. During hypertonicity, an increased ADH concentration would enhance the renal free water reabsorption. A net free water gain results in normalization of the plasma hypertonicity. 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