renal lithium excretion in man - semantic scholar · the observations may form the basis of a...

AMERICAN JOURNAL OF PHYSIOLOGY Vol. 215, No. 4, October 1968. Printed in U.S.A.

Renal lithium excretion in man

KLAUS THOMSEN AND MOGENS SCHOU Psychopharmacology Research Unit, Aarhus Uniuersity Psychiatric Institute, Risskov, Denmark

THOMSEN, KLAUS, AND MOGENS SCHOU. Renal lithium excretion k man. Am. J. Physiol. 215(4): 823-827. 1968.--Renal clearances of creatinine, lithium, sodium, and potassium were determined in six healthy human subjects. Lithium excretion was not significantly affected by water diuresis or the administration of furosemide, bendroflumethiazide, ethacrynic acid, ammonium chloride, spironolactone, or potassium chloride. Sodium-poor diet led to decrease and extra dietary sodium chloride to increase of lithium excretion; the changes took place relatively slowly. Osmotic diuresis (urea) and the administration of sodium bicarbonate, acetazolamide, and aminophylline all produced significant increase of lithium excretion. Lithium ions seem to be reabsorbed mainly in the proximal tubules. The observations may form the basis of a procedure for active treatment of lithium poisoning.

diuresis; diuretics; human kidney; drug effects, ghysiology, tubules; lithium poisoning; lithium, urine; tubular lithium reabsorption

L TITHIUM SALTS are being used increasingly in psychiatric therapy and prophylaxis, particularly as a maintenance treatment for recurrent manic-depressive disorder (2, 19). For full therapeutic and prophylactic effect the lithium content of the organism must be maintained at or above a particular level. Since only small amounts of lithium are lost with feces and sweat, maintenance of a proper lithium concentration depends on equilibrium between dosage and rate of excretion through the kid- neys. It is therefore important to know the factors that influence renal lithium elimination.

Lithium poisoning due to overdosage may be seen occasionally, and its course is determined prirnarily by the rate of renal lithium elimination (20). A search is therefore indicated for procedures that could raise the lithium clearance.

Renal lithiurn elimination has been the subject of a number of reports but is still insufficiently understood. In the present paper, renal lithium excretion has been studied in relation to the excretion of water, sodium, potassium, and hydrogen. Since data from animal experiments may not be applicable to man, the experiments were performed on human subjects.

METHODS

The studies were carried out on six healthy adult human subjects. During the clearance periods as well as during the days preceding them none of the subjects took drugs other than those that were part of the experiment. Unless otherwise indicated, the subjects ate ordinary mixed diets, which they salted according to individual tastes. They avoided coffee, tea, and other drinks which contain caffeine.

Clearances of creatinine, lithium, sodium, and potassium were determined in 7-hr periods. On the evening preceding the experiment, i.e., about 10 hr before the start of the clearance period, the subject swallowed two tablets each of which contained 300 mg of lithium car- bonate; the amount of lithium ingested was 16.2 mEq. At the start of the clearance period the subject emptied his bladder, and a blood sample was drawn from the ear lobe for deterrnination of serum creatinine, lithium, sodium, and potassium. The subject then collected urine quantitatively for 7 hr, and at the end of the period a second blood sample was drawn for lithium determination. Serum lithium decreased exponentially during the clearance period. In the first sample, concentrations ranged between 0.50 and 0.25 mEq/liter and in the second between 0.38 and 0.15 rnEq/liter.

Serum and urine concentrations of lithium, sodium, and potassium were determined with an Eppendorf flame photometer, with the use of appropriate standards and a method for serum lit.hium that was adapted to samples of 50 pliters ( 1). Under the experimental conditions employed, lithium determinations were carried out with relative standard deviations of less than 2 %.

Determinations of creatinine concentrations in serum and urine were performed according to the method of Bonsnes and Taussky (3), modified for use with small samples. The relative standard deviation was less than 3 %. Endogenous creatinine chromogen clearance was used as a measure of glomerular filtration rate (5). All determinations were carried out in duplicate.

Clearances were determined under control conditions, i.e., as described above, and under the influence of procedures that led to changes in the renal excretion of water, sodium, potassium, and hydrogen Table 1 shows the procedures and doses employed. Control periods,

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824 EL THOMSEN AND M. SCHOU

TABLE 1. E xjxrimental procedures emphyed TABLE 2. Changes of lithium, sodium, and potassium clearance during clearance determinations r&s produced by the e x@mental procedures

Subject

sex Age, yr Body wt, kg Height, cm

Experimental procedure

Water loading, liters

Furosemide, me Bendroflu-

methiazide,

mg Ethacrynic

acid, mg Ammonium

chloride, g Spironolac-

tone, mg Sodium bicar-

bonate, mEq Acetazol-

amide, mg Urea, g Aminophyl-

line, g

MS KT ELK AK EA KS ~~

M M F M F F 48 26 25 24 22 21

72 69 51 68 51 52

178 175 163 170 161 172

80 7.5

7 7 7

80 80 40 7.5 7.5 7.5

100 50 50 100

5 10 7.5 5

100 100 100 100

245 245 245 245

750 750 750 500

83 60 75 75 1.0 1 .o 1.0 1 .o

Total dose for each subject

-

-

40 7.5

100

750

7

80 7.5

50

5

100

245

500

75 0.5

five for each subject, alternated with experimen .a1 periods. Jn the experiments with water loading the subjects drank 1 liter of water/hr throughout the clearance period. Furosernide, bendroflumethiazide, ethacrynic acid, spironolactone, acetazolamide, and aminophylline were each given by mouth in a single dose at the start of the clearance period. Ammonium chloride, sodium bicarbonate, and urea were given in hourly doses during the first 5 hr of the clearance period.

The effect of variations in sodium chloride intake was studied in a separate set of experiments. One of the subjects spent 2 weeks on a sodium-poor diet (23); during a later period his ordinary diet was supplemented with sugar-coated tablets of sodium chloride in a dosage of 500 mEq/day. The subject drank water freely throughout both periods. Clearance deterrninations (7-hr periods) were carried out at intervals during the various dietary regimens.

RESULTS

During the control periods, average lithium clearances for the six subjects were 20, 23, 22, 25, 19, and 19 ml/min, respectively; standard deviations about 2 ml/min. The corresponding excretion fractions (C,i/C,,) were 0.17, 0.18, 0.23, 0.19, 0.23, and 0.17; standard deviations about 0.02 lntraindividual variation was generally smaller than interindividual variation; for each subject the changes produced by the experimental procedures were therefore calculated as percent of his or her mean

Experimental Procedure CLi/CCr CKa/CCr CKKC r

Water loading -8 0 70* Furosemide -11 220t w Bendroflumethiazide -2 180t 60* Ethacrynic acid - 2 280" 8W Ammonium chloride 2 20 10 Spironolactone 16 7ot -10 Sodium bicarbonate w 150 60* Acetazolamide 31* 120* 160t Urea 36* 10 0 Aminophylline -t 210* 401

For each subject the changes were calculated as percent of the mean control value. Figures in the table are average values for all subjects. *‘p < .05. tP < .Ol. $P < .OOl.

control value. Table 2 shows the average values of the changes for all subjects. Creatinine clearances were not affected by the experimental procedures.

Water loading led to an increase of urine flow of more than 1,000 % but did not affect lithium excretion. Administration of furosemide, bendroflumethiazide, and ethacrynic acid led to pronounced increase of urine flow and sodium output and some increase of potassium output, but left lithium excretion essentially unchanged. During administration of ammonium chloride, urinary pH decreased to values of 4.9-5.6; lithium excretion remained unaffected. After administration of spironolactone an increase of the lithium excretion could be noted, but it was not statistically significant. Administration of sodium bicarbonate and acetazolamide produced a rise of urinary pH to values of 7.0-8.0; urine flow, sodium output, and potassium output all increased. Under these conditions there was a 27-31 %> rise in the lithium excretion fraction. Still larger increases were produced by administration of urea and aminophylline. Both procedures led to increased urine flow; urea produced no change of sodium and potassium output, aminophylline an increase of both. Intake of other xanthines, e.g., caffeine, also led to an increase in lithium excretion.

Studies were further carried out with administration of mercurial diuretics and potassium chloride. The oral intake of chlormerodrin in doses of 75-100 mg led to significant increase of urine flow and sodium output in only two of the six subjects; in no case was the excretion of lithium changed. Due to the occurrence of side effects, higher doses of chlormerodrin were not employed. Enteric coated tablets of potassium chloride were given for 24 hr in doses which during the last 7 hr of the period led to a 100-200 !% increase of urinary potassium output; the procedure did not alter lithium excretion.

Urinary sodium output varies with sodium intake, but the changes are relatively slow. When sodium chloride was administered by mouth during the clearance period in doses equal to or higher than those of sodium bicarbonate, no significant change of sodium output was


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RENAL LITHIUM EXCRETION IN MAN

0.3

cLi C Cr

0.1

l l mm

l

l l l l

l l l l l

:m 0

:

l l l

l l l l

l

i

‘: l

200

Urinary Na output

600 800

(mEq/24h)

FIG. 1. Relation of lithium excretion fraction (C,i/Cc,) to urinary sodium output under dietary regimens with varying sodium intake.

produced. The effects of variation in sodium intake were therefore studied separately as described in METHODS.

Under ordinary dietary conditions the subject (KT) had a sodium intake of about 200 mEq/day. When he changed to a sodium-poor diet, his sodium output fell to less than 2 mEq/day and his body weight decreased within 3-4 days by about 2 kg. On resumption of his ordinary diet, the body weight rose by the same amount within 2 days. During the period with high intake of sodium chloride, the subject gained 3 kg and felt dis- tended. Results of this experiment appear in Fig. 1, in which lithium excretion fractions are plotted against urinary sodium output. It is noted that the excretion fraction varied considerably under conditions of varying sodium intake. It rose to 0.3 during salt loading and fell to less than 0.1 during sodium deprivation. The changes corresponded to approximately -50 and +50%, respectively, of the excretion fractions during control periods.

DISCUSSION

Experiments with filtration of plasma through cellulose membranes (8) show that lithium is not bound to plasma proteins; it therefore passes freely through the glomerular membranes.

Taking creatinine clearance as a measure of glomerular filtration rate, we find that about 80 c/c of the filtered lithium is reabsorbed in the tubules and 20 % excreted in the urine. The relation of lithium clearance and excretion fraction to the concentration in plasma was studied in dogs by Talso and Clarke (24), who found a low coefficient of correlation. Schou ( 16), working with rats, also noted a pronounced scatter but nevertheless felt that an inverse relation between excretion fraction and plasma concentrati .on could be discerned. However, since the da ta included clearanc e periods with low- and

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high-sodium intakes, the excretion .of lithium was under the influence of factors other than variation of plasma lithium concentration. Foulks et al. (8) infused lithium intravenously into dogs. In experimental periods during which the infusion of lithium was not accompanied by the administration of other electrolytes or drugs, the excretion fraction remained relatively constant over a wide range of plasma lithium concentrations ( 1-22 mEq/liter). In unpublished studies on human subjects, the present authors have found lithium clearance and excretion fraction to be independent of serum lithium within a range of at least 0.05-2.0 mEq/liter. As mentioned above, serum lithium concentrations in the present experiments varied between 0.15 and 0.50 mEq/liter.

The observation that renal lithium clearance is independent of the plasma concentration led Foulks et al. (8) to suggest that lithium reabsorption may be accomplished by a process of passive backdiffusion. This is not in agreement with other observations. If the reabsorption of lithium were due mainly to passive backdiffusion, the excretion fraction would vary with the rate of water excretion. That this is not the case is apparent from animal experiments in which urine flow was varied over a wide range ( 16, 24) and from the present observations with water loading.

Lithium is a monovalent cation and enters into the cells (15, 17). 0 ne might surmise that it was treated in the kidney in the same way as potassiuln, but this is not so. In stop-flow experiments with CK/Cc, values greater than one, Homer and Solomon ( 10) found no evidence of tubular secretion of lithium. Also, animal studies (8, 24) as well as the observations presented here show that procedures which markedly increase the excretion of potassium do not affect lithium excretion. Increase in hydrogen ion excretion, produced through administration of ammonium chloride, is also without effect on the excretion of lithium in the urine.

On the basis of determinations of lithium excretion fractions under varying sodium loads, Schou ( 16) sug- gested that lithium and sodium might be reabsorbed by common mechanisms, only lithium much less efficiently than sodium. In the light of the observations presented here this view is no longer tenable. If the same mechanisms were responsible for reabsorption of lithium and sodium, factors that affected the excretion of one ion should also affect the excretion of the other. Our experiments show that this is not the case. Furosemide, bendroflumethiazide, and ethacrynic acid produced marked increases of sodium excretion but did not alter lithium excretion. Administration of urea led to a significant rise of lithium excretion but almost no change in sodium excretion.

However, tubular reabsorption of sodium is accomplished through a series of absorptive processes along the nephron, and it seems possible that lithium may be reabsorbed via one or more of these and rejected by others. Available evidence is compatible with such an assumption.

Administration of urea, which is reabsorbed more


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826 K. THOMSEN AND M. SCHOU

slowly than water, leads to a decrease of fractional proximal sodium reabsorption, presumably caused by reduction of sodium concentration in the tubular fluid and more rapid passage of the fluid ( 12). This is counter- acted by distal reabsorption, which can work against a high conccn tr *ation gradient, and net excretion of sodium in t-he urine may therefore remain unchanged during urea-induced diuresis.

It appears from our experiments that lithium is treated differently; osmotic diuresis produces a significant rise of the excretion in the urine, and one therefore conclude that lithium is not rea bsorbed d

must s tallv .I

or is reabsorbed with low efficiency. This is supported by the experiments which show that interference with hydrogen and potassium excretion and so with linked sodium reabsorption in distal convoluted tubules and collecting ducts does not lead to alteration of lithium excretion.

The hypothesis may seem in disagreement with data obtained by Homer and Solomon ( 10) - They performed stop-flow studies in dogs and concluded from their observations that lithium is reabsorbed at the distal portion of the nephron, close to the site of sodium and potassium reabsorption and possibly by a common mechanism with poor discrimination between However, the demonstration

these monovalent cations. that lithium may be reab-

sorbed distally under stop-flow conditions is not incom- pati ble with the assumption that distal reabsorption of lithium plays only a minor role when the flow is un- impeded.

Solomon (22) infused isotonic solutions of various alkali metal chlorides into dogs and studied the cortico- papillary ion gradients by tissue analysis. Lithium concentration was found to increase from cortex to papilla, indicating that this ion is treated in the same way as sodium in the countercurrent transfer system of Henle’s loop. Furosemide, cthacrynic acid, and bcndroflu- mcthiazide all act on the ascending limb of the loop, the two first on both rnedullary and cortical segments, the third only on the cortical (21). The failure of these drugs to raise lithium excretion indicates that lithium is rcjccted by the rcabsorptive mechanism in the cortical segment and that reabsorption in the mcdullary segment, where countercurrent proccsscs arc at: work, does not affect net excretion significantly.

The assumption of a predominantly proximal reabsorption of lithium with sodium is in agreement with the observation that the fraction of filtered lithium which is reabsorbed through the entire length of the tubules is approximately the same as the fraction of filtered sodium which is reabsorbed in the proximal tubules. It is also compatible with the observation of a rise in lithium

REFERENCES

1. AMDISEN, A. Strum lithium determinations for clinical use. Stand. J. Clin. Lab. Invest. 20: 104-108, 1967.

2. BAASTRUP, P. C., AND M. SCHOU. Lithium as a prophylactic agent. Its effect against recurrent depressions and manic-depressive psychosis. Arch. Gen. Psychiat. 16 : 162-l 72, 1967.

excretion fraction after administration of aminophylline. Although the question whether aminophylline exerts an action on distal reabsorption of sodium has not been fully clarified, observations concerning its effect on free- water clearance indicate that in the proximal tubules it does lower fractional sodium reabsorption (9, 11).

The rise of lithium excretion observed after administration of sodium bicarbonate or carbonic anhydrase inhibitor might be a result of the rise of urinary pH, but this does no2; appear likely since lowering of pH was found to be entirelv without effect on lithium excretion. It is more plausible that the increase of the lithium excretion is due to an obligatory excretion of cation with unreabsorbed bicarbonate anion; reabsorption of bicarbonate takes place mainly in the proximal tubules. This interpretation of the data is supported by the observation (8) that infusion of sodium thiosulfate, which also leads to obligatory anion excretion, produces a significant rise in the excretion fraction of lithium.

Fractional reabsorption of lithium was found to vary with the dietary intake of sodium. During this experiment the subject had free access to water, and the rapid changes of his body weight presumably represent fluid loss and fluid retention. Under these circumstances alterations of extracellular fluid volume and third factor activity seem likely; the change of fractional lithium reabsorption may therefore reflect variation of proximal sodium reabsorption (6, 7, 13, 25). Direct evidence that changes of dietary salt intake influences sodium reabsorption in the proximal tubules is provided by studies on uremic patients receiving fluorohydrocortisone (4).

Oral administration of sodium chloride was previously advocated in the treatment of lithium poisoning ( 18). The present experiments confirm that this leads to a rise in lithium excretion, but the effect sets in slowly, and clinical experience has shown the procedure to be of limited practical value (20). Stronger and more rapid action might be obtained by infusion of sufficient quan- tities of saline, but in severely poisoned patients this procedure would entail risk of development of lung and brain cdcma.

Osmotic diurcsis, alkalinization of the urine, and administration of aminophylline exert a rapid action on lithium excretion and may be used individually or together. In Scandinavia a combination of the first two has proven safe and reliable as a standard procedure for the treatment of barbiturate poisoning ( 14), and recent experience with cases of lithium poisoning has shown that infusion of urea and sodium lactate can raise lithium excretion by 100-200 % (Myschetzky, Amdisen, Thomsen, and Schou, unpublished data).

3. BONSNES, R. W., AND H. H. TAUSSKY. On the calorimetric determination of creatinine by the Jaffe reaction. J. Biol.

Chem. 158: 581-591, 1945. 4. BRICKER, N. S. The control of sodium excretion with normal

and reduced nephron populations. Am. J. Med. 43 : 313-32 1, 1967.


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DIRKS, J. H., IV. J. CIRKSENA, AND R. W. BERLINER. The effect of saline infusion on sodium reabsorption by the proximal tubule of the dog. J. Cl&. Invest. 44: 1160-l 170, 1965. FOULKS, J., G. H. MUDGE, AND A. GILMAN. Renal excretion of cation in the dog during infusion of isotonic solutions of lithium chloride. Am. J. physiol. 168: 642-649, 1952. GOLDSTEIN, M. H-, M. F. LEVITT, A. D. HAWSER, AND D. POLIMEROS. Effect of meralluride on solute and water excretion in hydrated man: comments on site of action. J. Clin. Invest. 40: 731-742, 1961. HOMER, L. D., AND S. SOLOMON. Stop-flow studies on renal handling of lithium ions in the dog. Am. J. Physiol. 203: 897- 900, 1962, KLEEMAN, Ca R., R. CUTLER, M. I-3, MAXWELL, L. BERNSTEIN, AND J. T. DOWLXNG. Effect of various diuretic agents on maxi- mal sustained water diuresis. J. Lab. C&n. Med. 60: 224-244, 1962. KRUH#FFER, P. Studies on Water-Electrolyte Excretion and Glomeru- lar Activity in the Mammalian Kidney. London : Lewis, 1950. LANDWEHR, D. M., R. M. KLOSE, AND G. GIEBISCH. Renal tubular sodium and water reabsorption in the isotonic sodium chloride-loaded rat. Am. J. Physiol. 212 : 1327-1333, 1967. MYSCHETZKY, A., AND N. A. LASSEN. Urea-induced, osmotic

diuresis and alkalization of urine in acute barbiturate intoxica- tion. J. Am. Med. Assoc. 185 : 936-942, 1963.

15. RADOMSKI, J. L., H. N. FUYAT, A. A. NELSON, AND P. K. SMITH. The toxic effect, excretion and distribution of lithium chloride. J. Pharmacol. Exptd. *Therap. 100 : 429-444, 1950.

16. SCIXKJ, M. Lithium studies. 2. Renal elimination. Acta Pharma- col. Toxical. (Copenhagen) 15 : 85-98, 1958.

17. SCHOU, M. Lithium studies. 3. Distribution between serum and tissues. Acta. Pharmacol. ‘I’oxI.col. (Copenhagen) 15 : 115-124, 195%

18. SCHOU, M. Lithium in psychiatric therapy. Stock-taking after ten years. Psychopharmacologia 1: 65-78, 1959.

19. SCHOU, M. Lithium in psychiatric therapy and prophylaxis. J. Psychiat. Res. 6 : 67-95, 1968.

20. SCHOU, M., A. AMDISEN, AND J. TRAP-JENSEN. Lithium poisoning. Am. J. Psychiat. In press.

21. SELDIN, D. W., G. EKNOYAN, W. N. SUKI, AND F. C. REC’TOR, JR. Localization of diuretic action frown the pat tern of water and electrolyte excretion. Ann. N. Y. Acad. Sci. 139: 328-343, 1966.

22. SOLOMON, S. Action of alkali metals on papillary-cortical sodium gradientof dog kidney. Proc. SW. i?xpt/. Biol. 125: 1183- 1186, 1967.

23. STEINESS, E., AND I. STEINESS. En natriumfattig, kalium- og protein-begraenset d&t for hzmodialyserede patienter. Bibl. Leger 159 : 67-88, 1967.

24. TALSO, P. J., AND R. W. CLARKE. Excretion and distribution of lithium in the dog. Am. J. Physiol. 166 : 202-208, 195 1.

25. WATSON, J. F. Effect of saline loading on sodium reabsorption in the dog proximal tubule. Am. J. Physiol. 210: 781-785, 1965.


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