Solute-Free versus Electrolyte-Free Water Clearance in the Analysis of Osmoregulation

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1 Original Paper Nephron 2002;91:51 57 Accepted: May 16, 2001 Solute-Free versus Electrolyte-Free Water Clearance in the Analysis of Osmoregulation Kurakazu Shimizu Takeshi Kurosawa Teizo Sanjo Masanobu Hoshino Tatsuya Nonaka Sumiyoshi Clinic Hospital, Mito, Fourth Department of Internal Medicine, Tokyo Women s Medical University, Tokyo, and Kikukawabashi Clinic, Tokyo, Japan Key Words Free water clearance W Water balance W Urea osmolar clearance Abstract Background: Although attention has recently focused on electrolyte-free water clearance (E-C H2 O) as a replacement for solute-free water clearance (C H2 O), especially from the viewpoint of plasma sodium regulation, a thorough comparison of the two has yet to be conducted. Methods: C H2 O and E-C H2 O were systematically compared in normal subjects in different diuretic stages, including furosemide-induced solute diuresis, and in patients with renal disease. Results: The normal renal ability to conserve free water based on E-C H2 O was only 41% of that based on C H2 O. E-C H2 O remained positive until the urinary osmolality exceeded 500 mosm/kg H 2 O, markedly different from the 300 mosm/kg H 2 O for C H2 O. The difference between E-C H2 O and C H2 O could ultimately be attributed to urea osmolar clearance, i.e., urea excretion rate/plasma osmolality, which accounted for about 40% of the osmolar clearance. C H2 O underestimated the free water clearance by about 1 ml/min on average at all diuretic stages. Conclusions: E-C H2 O is a more correct parameter than C H2 O with regard to the regulation of both plasma sodium and plasma osmolality. However, there is the opinion that the concept of E-C H2 O is difficult to understand and that E-C H2 O is still not a generally accepted parameter. It is expected that the results of the present study will lead to more general acceptance. Introduction Copyright 2002 S. Karger AG, Basel Osmoregulation of body fluid is almost entirely mediated by changes in water balance. By quantitatively describing body water, it is possible to attain a better understanding of the mechanisms involved. Solute-free water clearance, commonly referred to as free water clearance (C H2 O), has traditionally been calculated as an index for evaluating water balance and for analyzing osmoregulation. According to this clearance concept, if C H2 O is positive, free water is being excreted in the urine which tends to raise plasma osmolality (P Osm ) and plasma sodium concentration (P Na ). On the other hand, if C H2 O is negative, free water is being reabsorbed in the renal tubules which tends to lower P Osm and P Na. To directly determine how much free water is actually being excreted or reabsorbed, the clearance concept is very helpful. However, in recent years, it has been shown that this concept is not correct when viewed in terms of P Na regulation. When calculating C H2 O, urea is included as a urinary ABC Fax karger@karger.ch S. Karger AG, Basel /02/ $18.50/0 Accessible online at: Kurakazu Shimizu, MD Oshiage, Sumida-ku Tokyo (Japan) Tel./Fax , aquamoon@mui.bioglobe.ne.jp

2 solute. Although urea is the principal urinary solute, it is an ineffective osmole, and its urinary excretion does not affect P Na. Thus, in order to more accurately evaluate water balance, the new concept of electrolyte-free water clearance (E-C H2 O) was introduced by Goldberg [1]. Rose [2, 3], Narins and Reiley [4], and Shoker [5] further studied the significance of this concept by applying it to the evaluation of typical clinical examples of hyponatremia and hypernatremia. Recently, it was also confirmed that E-C H2 O provides better information than C H2 O in calculating the tonicity balance [6]. Nevertheless, the quantitative relationship or difference between E-C H2 O and C H2 O has not yet been systematically studied. For example, neither the formulaic relationship between the two nor even the relationship between urinary osmolality and E-C H2 O have been presented in the published literature. There also appear to be some discrepancies regarding the handling of urinary ammonium ions (NH + 4) and glucose in the calculation of E-C H2 O. Moreover, apart from P Na, it has yet to be discussed whether or not E-C H2 O should be used in terms of P Osm regulation. Thus, C H2 O is still occasionally used to evaluate the water balance, suggesting a lack of adequate knowledge regarding E-C H2 O and C H2 O. The purpose of the present study was to establish the quantitative and theoretical differences between E-C H2 O and C H2 O and to determine the best method for evaluating the water balance. Methods Subjects Healthy adult male volunteers participated in the study for protocol conditions (a) through (c). Written informed consent was obtained from each subject. The age ranged from 22 to 26 years. Results of physical examination and blood and urine tests were normal. The subjects were on an ordinary Japanese diet. Patients with chronic glomerulonephritis in several clinical stages participated in the study for protocol condition (a). Plasma creatinine was 1.7 B (SD) 0.7 (range ) mg/dl, blood urea nitrogen was 27.8 B 12.9 (range 15 61) mg/dl, and the creatinine clearance was 66 B 46 (range ) ml/min. Protocol Osmolality and electrolyte concentrations in serum and urine were measured under the following conditions: (a) Water restriction (26 normal subjects and 36 patients). After overnight water restriction, beginning at h, urine and blood samples were collected hourly between and h the next morning. (b) Water loading (5 normal subjects). At and 09.00, 20 and 10 ml/kg of water, respectively, was ingested, and urine samples were collected every min for min, until maximal water diuresis was reached. (c) Vasopressin V 2 antagonist administration (6 normal subjects). A nonpeptide V 2 receptor antagonist (OPC-31260) was injected intravenously (1.0 mg/kg), and samples were collected every min, as described in a previous report [7]. (d) Furosemide administration (11 normal subjects). Furosemide (40 mg) was injected intravenously. Urine samples were collected every 30 min for 120 min, beginning immediately before the injection. (e) Spot urine and blood samples were collected from patients with liver cirrhosis, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and adrenal insufficiency during their typical electrolyte conditions. Equations C Osm = U Osm V/P Osm (1) C H2O = V C Osm (2) E-C Osm = U Na+K V/P Na (3) E-C H2O = V E-C Osm (4) where U Osm, urinary osmolality (mosm/kg H 2 O); P Osm, plasma osmolality (mosm/kg H 2 O); V, urinary flow rate (ml/min); P Na, plasma sodium concentration (meq/l); U Na+K, urinary sodium plus potassium concentration (meq/l); C Osm, osmolar clearance (ml/min); C H2O, solute-free water clearance (ml/min); E-C Osm, electrolyte osmolar clearance (ml/min); E-C H2O, electrolyte-free water clearance (ml/ min), and U urea, urinary urea concentration (mmol/l). Measurements Serum and urine osmolality were determined by the freezing point depression method using an osmometer (3D2; Advanced Instruments, Needham Heights, Mass., USA). Urinary Na and K concentrations were measured using a flame photometer (775A; Hitachi, Tokyo, Japan). Serum Na and K concentrations were measured using an autoanalyzer equipped with ion-specific electrodes (ION-150AC; Jokoh, Tokyo, Japan). Serum and urinary levels of creatinine and urea were measured using an autoanalyzer (736-10; Hitachi). Data are expressed as mean values B SEM. Results Table 1 shows the differences between C H2 O and E- C H2 O with some other related parameters. The average value for E-C H2 O in maximally concentrated urine was 0.54 ml/min, while that for C H2 O was 1.32 ml/min. Thus, the negative E-C H2 O value, i.e., electrolyte-free water reabsorption (E-T H2 Oc), was only 41% of the corresponding C H2 O value (T H2 Oc). In other words, the free water clearance calculated using C H2 O overestimated the free water absorption by 2.4-fold. The difference between E-C H2 O and C H2 O roughly corresponded to U urea V/P Osm. The mean E-C H2 O under maximal water diuresis was 11% higher than the mean C H2 O. 52 Nephron 2002;91:51 57 Shimizu/Kurosawa/Sanjo/Hoshino/Nonaka

3 Figure 1a illustrates the relationship between U Osm and E-C H2 O. The U Osm corresponding to E-C H2 O = 0 was about 500 mosm/kg H 2 O. Not shown in the figure, the relationships between U Osm and C H2 O and between U Na+K and E-C H2 O showed essentially the same patterns, except that the U Osm corresponding to C H2 O = 0 decreased to 300 mosm/kg H 2 O by the downward shift and that the U Na+K corresponding to E-C H2 O = 0 was around 150 meq/l, as expected. As a result, for a U Osm of mosm/kg H 2 O, E-C H2 O is positive, while C H2 O is negative. As shown in figure 1b, patients with chronic renal disease cannot reabsorb any more electrolyte-free water when the maximum U Osm drops below mosm/kg H 2 O. Figure 2 illustrates the relationship between C H2 O and E-C H2 O. The regression line indicates that the slope approaches unity and that at C H2 O = 0, E-C H2 O is higher than C H2 O by 0.93 ml/min. The relationship between U Osm (mosm/kg H 2 O) and 2U Na+K plus U urea (mmol/l) under protocol conditions (b) and (c) (n = 72) was expressed by the following regression line: U Osm = 0.96 (2U Na+K + U urea ) 2.8 (r = 0.96) U urea = 0.42U Osm (r = 0.93) Table 1. C H2O, E-C H2O, and other related parameters under the conditions of overnight water restriction and maximal water diuresis Water restriction (n = 52) Maximal water diuresis (n = 5) V, ml/min 0.57B B0.7 U Osm, mosm/kg H 2 O 978B14 64B4 C H2O, ml/min 1.32B B0.6 E-C H2O, ml/min 0.54B B0.5 C Osm, ml/min 1.90B B0.28 E-C Osm, ml/min 1.11B B0.25 2U Na+K, meq/l 554B12 35B4 U urea, mmol/l 438B18 39B6 E-C H2O C H2O, ml/min 0.78B B0.22 U urea V/P Osm, ml/min 0.83B B0.26 Fig. 1. Relationships between U Osm and E-C H2O in normal subjects (a) and maximum U Osm and E-C H2O in patients with chronic renal disease (b). a Data from protocol conditions (b) (n = 35) and (c) (n = 37). b Data from protocol condition (a). CH 2 O versus E-CH 2 O Nephron 2002;91:

4 Fig. 2. Relationship between C H2O and E-C H2O. Data from protocol conditions (b) (n = 35) and (c) (n = 37). These equations indicate that at any given osmolality U Osm ] 2U Na+K + U urea (5) and that urinary urea accounts for about 40% of U Osm. Although the measured osmolality is slightly below the calculated osmolality, this can be explained by the osmotic coefficient for the ions in urine. A similar relationship was also seen in patients with chronic renal disease, suggesting that equation 5 is again applicable. U Osm = 1.12 (2U Na+K + U urea ) 11.7 (r = 0.95) U urea = 0.34U Osm +34 (r = 0.80) The effect of furosemide on E-C H2 O is illustrated in figure 3. Furosemide caused marked increases in V and in Na excretion and a decrease in U Osm to an isosmotic level. Although C H2 O remained negative, E-C H2 O changed from negative to positive. In addition, the increase in Na excretion per se was not selectively related to the change in E- C H2 O, since E-C H2 O minus C H2 O remained almost constant irrespective of urinary Na excretion, but corresponded well to U urea V/P Osm. Fig. 3. Effects of intravenous injection of furosemide (40 mg) on E-C H2O and C H2O. The theoretical relationship between E-C H2 O and C H2 O can be defined as follows: E-C H2O = C H2O + U urea V/P Osm (6) Equation 6 is obtained by substituting equation 5 and P Osm = 2P Na [3] into equation 1. Here, U urea V/P Osm is the portion of the urine volume that contains urea isosmotically with the plasma, and this component can be ex- 54 Nephron 2002;91:51 57 Shimizu/Kurosawa/Sanjo/Hoshino/Nonaka

5 pressed as urea osmolar clearance (urea-c Osm ), just as U Na+K V/P Na is expressed as E-C Osm. Thus, urea-c Osm is actually a component of E-C H2 O, while it was previously considered to be a component of C Osm. As indicated, under ordinary conditions, urea-c Osm ] 0.4C Osm. These theoretical results correlated very well with the measured data shown in table 1 and figure 3. Furthermore, the regression line in figure 2, i.e., E-C H2O = 1.05 C H2O (7) fits well into equation 6. Although the slope is slightly greater than unity, this may reflect the fact that the urea excretion rate increases as the urine flow rate increases [8, 9]. Although self-evident, the constant in equation 7 should be U urea V/P Osm at C H2 O = 0. This value was 0.96 B 0.13 ml/min when C H2 O was 0.29 B 0.05 ml/min (mean B SE, n = 6). Thus, C H2 O underestimates free water clearance by roughly 1 ml/min on average. Based on equations 5 and 6, the U Osm at which E-C H2 O becomes zero (U) Osm ) can be expressed as follows: U) Osm = P Osm /k (k = 2U Na+K /U Osm ) (8) Thus, U) Osm increases exponentially as the proportion of 2U Na+K in U Osm decreases and that of U urea increases. This is in sharp contrast to C H2 O which is always zero at U Osm = P Osm. Table 2 shows the percentage of 2U Na+K in U Osm and the calculated U) Osm in normal subjects and in patients with various diseases under typical electrolyte conditions. In patients with decompensated liver cirrhosis with low U Na+K, U) Osm is higher than 1,000 mosm/kg H 2 O. On the contrary, under solute diuresis by furosemide, U) Osm is much lower than under ordinary conditions. Discussion In the present study, the values for E-C H2 O and C H2 O were systematically compared. The results indicate that the renal ability of normal subjects to conserve free water, i.e., negative E-C H2 O, is much less than previously evaluated based on the calculation of C H2 O, actually less than half (41%) in maximally concentrated urine (table 1). Furthermore, E-C H2 O remained positive, until U Osm exceeded about 500 mosm/kg H 2 O. This is markedly different from the prevailing concept that when U Osm exceeds P Osm, C H2 O becomes negative and, therefore, free water is being reabsorbed and diluting body fluids [1, 10 12]. Table 2. Percentage of 2U Na+K in U Osm and U) Osm under various conditions 2U Na+K / U Osm, % U) Osm n (mosm/kg H 2 O) c Normal subjects a 57.9B Liver cirrhosis (decompensated) 21.5B3.3 1,326 5 SIADH 59.7B Adrenal insufficiency 70.0B Furosemide infusion b 93.7B a Data from protocol conditions (b) (n = 35) and (c) (n = 37). b At 60 min after furosemide injection (fig. 3). c U) Osm (mean U Osm at which E-C H2O becomes zero) was calculated by equation 8. These differences between E-C H2 O and C H2 O are of important physiological and clinical significance for the evaluation of water balance. For example, assuming a urine volume of 1.6 liters per day with a U Osm of 500 mosm/kg H 2 O, C H2 O would be calculated to be about 1.2 liters per day. In contrast, the results of the present study suggest that E-C H2 O is actually around zero (fig. 1a). Equation 7 would also give a similar result. Evidently, the calculation of E-C H2 O is quite consistent with the fact that plasma osmolality and Na concentration continue to increase during water restriction with an insensible water loss of about 1 liter per day [13]. Thus, under these conditions, C H2 O underestimates the free water clearance by about 1.2 liters per day. Furthermore, based on the concept of C H2 O, patients with chronic renal failure are believed to be able to reabsorb free water until finally the urine becomes isosmotic with the plasma. However, such patients are, in fact, obliged to excrete free water when the maximum U Osm drops below mosm/kg H 2 O (fig. 1b). Accordingly, these patients are more at risk of dehydration than previously thought, and a high protein intake may even increase the risk by raising this U Osm threshold (equation 8), with a possible increase in the proportion of urinary urea [14, 15]. From the viewpoint of P Osm regulation, the traditional theory of C Osm and C H2 O [16, 17] seems to be correct. However, it has been shown that, when viewed in terms of P Na, that the traditional concept is not correct [1 4]. The major urinary solutes are the salts of Na and K plus urea. Na and K ions are responsible for effective osmotic forces in the extra- and intracellular fluids. On the contrary, urea CH 2 O versus E-CH 2 O Nephron 2002;91:

6 is an ineffective osmole; it freely penetrates the cell membranes and does not displace water from one fluid compartment to another, and so its urinary excretion leaves P Na unchanged [1 4]. Therefore, urea should be eliminated from the calculation of C Osm. For these reasons, new formulas for E-C Osm and E-C H2 O (equations 3 and 4) were introduced [1, 2] (2U Na+K was substituted for U Osm and 2P Na for P Osm in equations 1 and 2). In this concept, E-C Osm is a component of urine volume that contains all of the urinary electrolytes isosmotic with 2P Na. Thus, when U Osm 1 P Osm, this suggests that vasopressin is having an effect. When U Na+K 1 P Na, E-C H2 O is negative. By calculating E-C H2 O, the rate of electrolyte-free water being reabsorbed or excreted can be determined. Since urea-c Osm is a component of E-C H2 O, an obligatory volume of free water must be excreted with urea. Thus, patients in a state of urea-osmotic diuresis can become hypernatremic from the loss of electrolyte-free water [18]. Urea has also been used therapeutically to raise P Na in patients with SIADH [19]. Under these conditions, the contribution of urea can be expressed as Urea V ] (U Osm 2U Na+K )V. Apart from P Na regulation, should C H2 O be used with regard to P Osm regulation? Urea excretion may lower the plasma urea concentration and thus lower P Osm. However, urea is constantly being produced in an amount almost equal to that excreted. Under these conditions, there is no net transfer of urea from the body fluids, and free water equivalent to urea-c Osm is excreted, so it is more accurate to use E-C H2 O. The urinary ammonium (NH + 4) concentration in normal daily urine remains constant at around 20 mmol/l [20]. Therefore, the contribution of NH + 4 to U Osm is so small that it can be ignored. However, urinary NH + 4 can increase to higher than 150 mmol/l during nonrenal metabolic acidosis [20]. Under this condition, NH + 4 should be included in the calculation of U Osm. Thus, U Osm ] 2U Na+K + U urea + 2U NH + 4. In this connection, it should be mentioned that urea becomes permeable when vasopressin acts on the collecting ducts, whereas NH + 4 is not permeable. However, NH+ 4 excretion has no major effect on either P Na or P Osm, since NH + 4 is ultimately produced in the renal tubules from precursor amino acids, and NH + 4 excretion is ultimately coupled with HCO 3 reabsorption [21]. Therefore, although NH + 4 is an impermeable osmole, it should be treated similarly to urea [6], i.e., omitted from the calculation of E-C Osm. Thus, NH + 4 is sometimes treated similarly to urea by being regarded as an permeable osmole [5]. However, there is also the opinion that NH + 4 should be included in the calculation of E-C Osm [12]. When stable hyperglycemia and glucosuria both exist, isosmotic glucose excretion can be regarded as a component of E-C H2 O, similar to as discussed above under the issue of urea and NH + 4 and free water loss should be calculated by E-C H2 O. Thus, glucosuria per se tends to increase P Na, as typically seen in glucose-osmotic diuresis [22 24], while hyperglycemia tends to decrease P Na by inducing water movement from the intracellular to the extracellular compartment [25, 26]. In contrast, glucose was included in the calculation of E-C Osm [5] which would seem to be valid under the premise that the plasma glucose concentration is mainly dependent upon urinary glucose excretion. C H2 O during maximal water diuresis has been used as an index of Na reabsorption in the diluting segments of the nephron [10 12]. E-C H2 O may be a more appropriate index than C H2 O, because E-C H2 O eliminates the effect of the change in the intratubular urea [15]. Even today, C H2 O rather than E-C H2 O is occasionally used in the evaluation of the water balance, suggesting that the concept of E-C H2 O has yet to be fully understood and generally accepted. In this context, unfortunately not all of the current nephrology textbooks contain an explanation of E-C H2 O. It has been commented that free water clearance adds no useful clinical information to the measurement of urine-specific gravity or osmolality [27]. Also, various abbreviations other than E-C H2 O, such as C e H 2 O [1, 3], C H2 O (E) [4], and EWC (effective water clearance) with a slightly different formula of EWC = V (1 U Na+K /P Na+K ) [5, 6], have been independently used to represent electrolyte-free water clearance, and it would be best if a single term and formula were selected. In conclusion, the present study clarified the quantitative and theoretical differences between E-C H2 O and C H2 O by a thorough comparison of the two, demonstrating the inappropriateness of analyzing osmoregulation based on the classical C H2 O. There is the opinion that the concept of E-C H2 O is difficult to understand, and in spite of frequent references in the literature, E-C H2 O is still not a generally accepted parameter. It is expected that the results of the present study will lead to more general acceptance and wider use of E-C H2 O. E-C H2O = C H2O + (U urea + 2U NH + 4 ) V/P Osm 56 Nephron 2002;91:51 57 Shimizu/Kurosawa/Sanjo/Hoshino/Nonaka

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