Eur J Clin Pharmacol (1990) 39:8%90

EuropeanJournalof ( ~ [ ~ ( ~ ( ~

@ Springer-Verlag1990

The use of a single non-timed urine collection in the calculation of fractional lithium clearance
M. O ' H a g a n and S. G r e e n e Department of Child Health, Ninewells Hospital and Medical School, Dundee, Scotland Received: May 19, 1989/Accepted in revised form: February 9, 1990

The fractional clearance of lithium (CLLi/CLcR) calculated in 15 normal healthy adults from a single morning urine aliquot collection, together with a single venous blood sample (FQ) was compared with the average CLLi/CLcR obtained from three timed consecutive urine collections with mid-point blood sampling (FABC). Lithium had been ingested 15-18 h prior to the collection of these samples. Mean CLLi/CLcR was similar (FQ, 0.186, FABC, 0.177), with a highly significant correlation in each individual of CLLi/CLcR measured by either method (r = 0.97, P < 0.0001). Proximal tubular reabsorption of sodium using lithium clearance may be calculated from a single urine and blood sample.

Summary.

the collection of the timed urine specimen with mid point blood sampling. Vincent et al recently reported a simplified method for evaluating proximal tubular fluid reabsorption [3] but they still required a short accurately timed urine collection. Acceptability of clinical studies to children and adults requires that urine and blood sampling is kept to a minimum. Daytime urine collections are notoriously inaccurate particularly in children. H o m e based investigations require very simple protocols. We therefore devised a study protocol to compare the CLu/CLcR calculated from a single morning urine aliquot collection with CLLi/CLcR derived from standard timed urine collections.

Subjects and method Key words: Lithium clearance; proximal tubule, sodium,
fractional clearance Fifteen healthy adult volunteers ingested lithium carbonate at a dose of 10 mg- kg- ~(not exceeding 750 mg in total) at 18.00 h with their evening meal. They were then allowed to ingest only water until mid-

The renal clearance of lithium has been established as a measure of the renal handling of sodium, with fractional clearance of lithium (ie. in relation to creatinine clearance, CLu/CLcR) taken as an equivalent measure of the fractional proximal tubular reabsorption of sodium (FracPTRNa) [1, 2]. The method is based on the assumption that lithium is exclusively absorbed in the proximal tubule and under physiological conditions this assumption has been validated as regards the convuluted portion of the proximal tubule [1]. Lithium clearance can be measured in the usual manner by measuring the amount of lithium excreted by the kidney in unit time (after ingestion of lithium) and dividing this value by the serum lithium concentration. Using this standard formula of UV/P for the calculation of renal clearance, the formula of fractional clearance is simplified to [ULi] x [PcR]/[PLi] [UcR], where [ULi] and [UcR] equal the urine concentration of lithium and creatinine respectively and [PLi] and [PcR] equal the plasma/serum concentration of lithium and creatinine respectively: the urine flow rate, V, is eliminated from the equation. Despite this simplification, clinical studies calculating FracPTRNa from the renal clearance of lithium have used

Table 1. The fractional clearance values (%) for the aliquot urine
specimen (Fo), each of the timed urine specimens (Fa, Fm Fc) respectively, and the mean fractional clearance of the 3 timed urine specimens (FABc)in each individual Patient Number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Mean (SD) Fo 17.4 23.8 10.0 23.4 14.1 28.6 20.0 17.9 12.4 14.4 20.8 24.6 16.3 20.4 15.7 18.6 (5.1) FA 17.4 23.8 10.0 23.4 14.1 28.6 20.0 17.9 12.4 14.4 20.8 24.4 16.3 20.4 15.7 FB 18.9 20.2 10.3 22.8 12.2 29.4 18.6 15.4 10.9 14.9 18.3 21.2 17.0 22.0 14.3 Fc 19.5 20.4 10.0 22.0 10.3 28.9 15.3 15.1 10.7 14.6 14.2 21.9 13.5 19.4 14.9 FABc 18.6 21.4 10.1 22.7 12.2 28.9 17.9 16.1 13.3 14.6 17.7 22.5 15.6 20.6 14.9 17.7 (5.0)

90
0.3

M. O'Hagan and S. Green: Fractional lithium clearance The fractional clearance for each timed urine specimen together with the aliquot is given in the table. No significant difference was noted between the m e a n (SD) of the aliquot CLL~/CLcR (FQ) (0.186 (0.51)) and the m e a n (SD) of the average CLLi/CLc~ calculated from the three morning urine collections (FABC) (0.177 (0.50)). A high correlation was seen between CLLi/CLcR calculated from the aliquot (FQ) and the m e a n of the timed urine specimens (FABC) in each individual. (Fig. 1)

0.26

0.22 -

FQ 0.18 -

Discussion
The high correlation coefficient and similar values of CLLi/CLcR calculated from the aliquot urine and the timed urine collection implies that an accurate measure of the fractional clearance of lithium can be obtained using only a single morning urine aliquot. The fact that to calculate the fractional clearance does not involve the need to know the volume of urine collected (see formula) makes the investigative procedure easier to perform as only one nontimed urine aliquot is required. Similarly only one blood sample is required given the constant concentration of lithium over the time period. This simplified protocol would therefore allow for the m e a s u r e m e n t of proximal tubular handling of sodium in large groups of subjects under a variety of conditions including h o m e based studies. A n example of such a study would be the investigation of renal handling of sodium in children and teenagers with insulin-dependent diabetes, or the assessment of renal salt handling in essential hypertension.

0.14 -

0.1

" I I I

0.1

0.14

0,18

0.22

0.26

0,3

FABC

Fig.1. The relationship between fractional clearance of lithium (CLLi/CLcR) calculated from a single morning urinary aliquot (FQ) and the average taken from three consecutive timed urine samples (FABC) in fifteen normal adults (r = 0.97, P < 0.001)

day the next day. There were no other restrictions and they continued with their normal working day. Four timed separate urine collections from 23.00-07.30 (O), 07.30-08.30 (A), 08.30-10.00 (B), and 10.00-12.00 h (C) were obtained from each individual. The 08.30 h urine was also used as a single aliquot urine (Q). Venous blood samples were taken at 08.30 and 11.00 h. Urine and serum creatinine and lithium levels were measured together with the volume of each urine collection. Lithium was measured by flame photometry and creatinine by a modified Jaffe technique [4]. Lithium and creatinine clearances were calculated for each separate timed urine collection (using UV/P) and again designated O, A, B, C with aIl values corrected to 1.73 m2SA. Fractional clearance for the urine aliquot [Q] was calculated without the measure of V, i. e. [ELi ] X [PcR]/[UcR] X [PLi]-

Acknowledgements. We thank Mrs Vera Murray for help in preparing this manuscript.

References
1. Thomson K (1984) Lithium clearance: a new method for determining proximal and distal tubular reabsorption of sodium and water. Nephron 37:217-233 2. Brochner-Mortensen J, Stockel M, Sorensen PJ, Neilsen AH, Ditzel J (1984) Proximal glomerulotubular balance in patients with type i (insulin-dependent) diabetes mellitus. Diabetologia 27:189-192 3. Vincent HH, Boer WH, Wenting GJ, Schaeletamp MADH, Weirmar W (1987) Simplified method for evaluating proximal tubular fluid reabsorption. Lancet I11456 4. Larsen K (1972) Creatinine assay by a reaction-kinetic approach. Clin Chem Acta 41:209-217

Results
The serum creatinine of each individual was within the normal range and ranged from 60-118 gmol.1-1. The serum lithium level taken at 08.30 h in each individual was nearly identical to the sample taken at 11.00 h. (Mean (SD) 08.30 h = 0 . 2 4 (0.47), 11.00 h =0.22 (0.45) mmol1-1). As blood and urine lithium concentrations would decline during the 12 h following ingestion the overnight samples were not included in the calculation of fractional clearance.

Dr. M. O'Hagan Department of Child Health Ninewells Hospital and Medical School Dundee DD1 9SY Scotland UK