.. .
-a
Kidney functioninrr during lithium treatment: a prospective study of patien treated with lithium for up to ten years U
..
Povlsen UJ, Hetmar 0, Ladefoged J, Bolwig TG. Kidney functioning during lithium treatment: a prospective study of patients treated with lithium for up to ten years. Acta Psychiatr Scand 1992: 85: 56-60. A cohort of 53 patients with affective disorders who originally carried through renal functional tests before start of prophylactic lithium treatment were followed up prospectively after an average period of 8.5 years (range 7-10 years). Ten patients who had continued lithium treatment were re-examined. In this subgroup, the glomerular function was unaffected by the treatment, whereas the average urine volume increased during lithium treatment (NS). Polyuria and low renal concentrating abilities were also found before start of treatment and these findings underline the importance of access to renal baseline information prior to lithium treatment.
The prophylactic effect of lithium in manic-depressive illness is by now one of the best documented in psychiatric pharmacotherapy (1,2). In clinical practice it was accepted that thirst and polyuria would develop in many patients on lithium, a complication attributed to decreased responsiveness of the renal tubules to antidiuretic hormone. These unwanted effects were regarded as strictly functional and fully reversible and therefore unlikely to be associated with morphological abnormalities. In 1977,however, evidence of a chronic interstitial nephropathy was reported in a small number of patients with lithium intoxication and/or marked polyuria (3). These reports initiated a large number of systematic studies on the renal impact of lithium treatment (4, 5). In general, no significant deterioration in glomerular filtration rate has been shown, whereas a decrease in renal concentrating capacity in a majority of patients on long-term lithium treatment has been reported (6). Most of the clinical studies have been crosssectional and therefore of limited value, since it is impossible to conclude whether the observed values are associated with lithium. Prospective studies providing baseline information on glomerulotubular function before start of treatment and using patients as their own controls during treatment enable definitive identification of a putative lithium-induced renal impairment of a progressive nature. Studies using this method are few in number and generally the observation periods have been short: 1 year (7), 2 years (8), 3 years (9) and 7 years (10). 56
’,
’,
U. J. Povlsen 0. Hetmar J. Ladefoged T. G. Bolwig
’, ’
’
Departments of Psychiatry and Nephrology, Rigshospitalet, University of Copenhagen, Denmark
Key words: lithium prophylaxis; renal functioning; longitudinal study Uffe Juul Povlsen, M.D., Department of Psychiatry, 6223, Rigshospitalet. Blegdamsvej 9, DK-2100 Copenhagen, Denmark Accepted for publication August 9, 1991
This article presents a prospective follow-up study of 53 pre-lithium control patients, some of which have now been in lithium treatment for 10 years, with special emphasis on renal functioning. Material and methods Pre-lithium examination
The original sample was established from September 1977 to October 1980 in the Department of Psychiatry, Rigshospitalet, Copenhagen, Denmark, and consisted of 53 patients with a diagnosis of affective disorders (ICD 296), never treated with lithium but selected because commencement of prophylactic treatment was under consideration. Mean age at the pre-lithium examination was 40 years (range 19-7 1); 33 patients were women, 20 men. None of the patients had a past history of renal disease, cardiovascular disorder or diabetes mellitus. The average number of affective episodes was 7 at the time of the baseline investigation. Two patients had only had manic episodes, 23 patients depression and 28 patients were bipolar. At the time of the pre-lithium examination most of the patients, 38/53, were on additional psychopharmacological treatment, either antidepressants alone or in various combinations with antipsychotic medication. FOIIOW-UP study
From October to December 1987 a follow-up investigation of the original sample was carried out.
Kidneys and lithium Forty-three patients of this sample began lithium treatment and 7 patients never started lithium, partly because of change of diagnosis or because the patients became stable during treatment with tricyclic antidepressants. Three patients moved to other regions and no data about lithium treatment were available. Thirty patients (19 women, 11 men) had stopped their lithium treatment after an average of 2.6 years (range 0.2-8.2). The main reasons for discontinuation of lithium were side effects in 6 patients, insufficient therapeutic effect in 2 patients, a general aversion to lithium in 7 and diagnostic re-evaluation in 5 patients. Another 2 patients stopped lithium in relation to suicidal behavior, and lithium was discontinued in relation to pregnancy in 2 patients. No follow-up data were available on 6 patients. Thirteen patients who had continued lithium treatment were invited to participate in a re-examination of kidney functioning. Ten patients agreed to take part. Informed consent was obtained from all. Exactly the same renal functional tests as in the prelithium examination were performed during a 5-d admission to the Psychochemistry Research Ward, Rigshospitalet, which has metabolic facilities to ensure complete urine collection. Analyses and functional tests
Two clearances were performed: 1. Endogenous creatinine clearance: urine was collected quantitatively for three 24-h periods and creatinine clearance was calculated from the urine and serum creatinine. Median values were used in the statistical analysis. 2. Lithium clearance (CLi): the patients were instructed to empty their bladders at 0800 and to collect all subsequent urine for the next 24 h divided in the following periods: 1) 0800-1500, 2) 1500-2200 and 3) 2200-0800. Blood samples were taken at 0800, 1500 and 2200. CLi was calculated as follows: cu x
v
ACp x time
=
CLi,
where Cu = lithium urine concentration and V = urine volume. A Cp equals the regressed serum lithium level at the midpoint of the period as expressed by the following equation: Cp (start of period) - Cp (end of period) 2.3 x log (Cp (start of period)/Cp (end of period)) The mean lithium clearance of the 3 periods was then calculated considering the length of the period (in hours):
c
.=
7 x CLi(1)
+ 7 x CLi(2) + 10 x
CLi(3))
L1
24 All clearances were expressed as ml/s. Renal concentration capacity was determined by a 26-h water deprivation test. The period was shortened to 8 h if a patient lost more than 3% of body weight during the first 8 h of water deprivation. Serum and urine osmolality was determined by a Knauer Osmometer and expressed as mosmol/kg H,O. Statistical analysis
Nonparametric statistical tests (Mann-Whitney, Wilcoxon’s test) were applied when direct ungrouped observations were compared. For grouped data, ordinary chi-square tests for contingency tables were used or, in case of sparse data, generalized Fisher’s exact test. All statistical tests were two-tailed and evaluated with respect to significance at 5 % . Test results are reported using significance probabilities. Results
All 10 patients (6 women, 4 men) had continued their lithium treatment without known interruptions, and no symptoms of lithium intoxication had occurred. Serum lithium monitoring was performed every third to sixth month. Mean age at the followup investigation was 47 years (range 34-65) and the average duration of lithium treatment was 8 years (range 7-10). At steady-state the serum lithium levels was 0.77mmol/l (range 0.66-0.92) and the average lithium dosage was 23.4 mmo1/24 h (range 1632). All patients were on a single-dose schedule taking either conventional carbonate tablets (7 patients) or a sustained-release lithium citrate preparation (LitarexO, 3 patients). Two patients were treated with lithium only, whereas 5 patients concomitantly received tricyclic antidepressants and 3 patients both antidepressants and antipsychotic preparations. During the follow-up period half of the patients had no admissions to psychiatric hospitals, whereas the other half had a total of 18 admissions (mean 3.6; range 1-6). Serum creatinine increased significantly from 0.087 mmol/l (range 0.07-0.11) at the pre-lithium test to 0.099 mmol/l at retest (range 0.09-0.14; P = 0.02 (Wilcoxon’s test)). One male patient had a serum creatinine value that exceeded the normal range (0.14 mmol/l). In our laboratory the normal range is 0.06-0.13 mmol/l for men and 0.040.1 1 mmol/l for women. Urine volume increased from a mean pre-lithium value of 2053 m1/24 h (range 1328-4100) to 2519 ml/ 57
Povlsen et al. 24 h (range 1630-4620) on lithium maintenance ( P = 0.06 (Wilcoxon’s test)). A marked change was seen in 1 patient, who had an increase in urinary output from 2690 to 4620 m1/24 h, respectively. Another man had a remarkably high urine volume before start of lithium treatment (4100 m1/24 h), but no significant change was seen on lithium. Maximum renal concentrating capacity was determined in 7 patients before lithium treatment (mean 847 mosmol/kg H,O; range 649-989) and in 6 patients during lithium treatment (mean 868 mosmol/ kg H,O; range 675-1090). Only minor changes were found. Two patients had urine osmolalities below 800 mosmol/kg H20. Endogenous creatinine clearance decreased from a pre-lithium value of 1.77 ml/s (range 1.34-2.70) to a lithium value of 1.70 ml/s (range 1.11-2.49) ( P = 0.17 (Wilcoxon’s test)). Two patients on lithium had creatinine clearances below normal range (1.1 1 and 1.27 ml/s, respectively). Renal lithium clearance decreased from 0.46 ml/s (range0.26-0.82) at the first investigation (n = 7) to 0.42ml/s (range 0.30-0.61) at the follow-up ( n = 10) (NS). Discussion
This longitudinal study presents prospective renal functioning tests and retrospective clinical data from a cohort of 53 patients with affective disorders, who were examined about 10 years ago because commencement of lithium treatment was considered. Subsequently, 10 patients out of this cohort were continuously treated with lithium for an average of 8 years (range 7-10). Our study showed no significant impairment of tubular functioning following lithium treatment. Although the average urine volume increased from 2 to 2.5 1/24 h, the difference was not significant. Maximum renal concentrating capacity was almost unchanged during the follow-up period, both in terms of mean values and intraindividual differences. Impairment of renal concentrating capacity has been the most consistent finding in cross-sectional as well as longitudinal studies (1 1-14), but the prevalence and reversibility is still uncertain. In a total of 1105 unselected lithium-treated patients, 54 % had a subnormal concentrating capacity relative to normal ranges (4). However, the impairment of concentrating capacity was reported to be mild or moderate in other studies (15, 16). The impact of lithium on tubular functioning depends on various factors. First, the action of lithium may depend on lithium dosage schedule. Recent studies suggest that renal functioning and structure is less affected in organisms receiving lithium once a day compared with patients given lithium in 2-3 divided daily doses 58
(17, 18). In the present study, all patients had received lithium in a single daily dosage and had followed the same regimen throughout the entire treatment period, which may explain the relatively unaffected tubular functioning. However, the number of patients and the non-allocated design of the study do not allow any definitive conclusion. Second, the impact may depend on lithium dosage. Our clinic, like many other, has gradually adopted lower lithium levels and the serum lithium concentrations used in this study were generally lower than those in our retrospective functional study (14), which may explain the differently affected concentrating capacity. Third, the impairment of concentrating capacity may not be specifically related to lithium, but also to other factors associated with affective illness. Controlled studies have shown that renal concentrating capacity was impaired in both lithium and nonlithium-treated control patients, but the difference was not significant, and all groups had mean values below 800mosmol/kg H 2 0 (15, 16, 19). This is in agreement with a renal biopsy study by Walker et al. (20), who compared renal biopsies from 47 lithiumtreated patients with specimens from 32 patients with affective disorders who had never received lithium. No difference in the percentage of interstitial fibrosis between the 2 patients groups was found, which questions the relationship between lithium and structural renal changes, but might explain the reduced concentrating capacity found in other patients not treated with lithium. However, other studies have reported a significantly lower maximum renal concentrating capacity in lithium-treated patients than in affectively ill control patients receiving other drugs (12, 18, 21-23). In our study, 2 patients had subnormal concentrating capacity. One patient was a 38-year-old male who was permanently in treatment with 150-200 mg imipramine per day and had complaints of thirst and dry mouth. The reduction in concentrating capacity at the initial investigation corresponded to polyuria (4100 mo1/24 h), which did not increase after 9 years on lithium (3800 m1/24 h). He was unable to carry through the fluid deprivation test because of dizziness and nausea. Another patient had developed polyuria after start of lithium treatment and was also unable to complete the thirst test because of weight loss. About 6-7 years previous to the re-examination, he had developed arterial hypertension and was periodically in treatment with diuretics, but not at the follow-up investigation, and his polyuria is probably unrelated to lithium. The importance of access to renal baseline information prior to lithium use is underlined by these cases. The study revealed a significant increase in mean serum creatinine from 0.087 to 0.099 mmol/l, but
Kidneys and lithium only a single value was marginally increased. However, determination of serum creatinine is a rather inaccurate measure for glomerular functioning and the decrease in mean endogenous creatinine clearance from 1.77 to 1.70 mljs was not greater than might be expected from increasing age (10 ml/min/ decade (24)). Two patients had clearance values below 1.30 ml/s, but both had normal renal lithium clearances. During lithium treatment all 10 patients had lithium clearances within normal range (0.170.67 ml/s). Our study speaks against any significant deterioration in glomerular functioning during lithium treatment for an average of 8 years, which is in agreement with other prospective studies (8, 10) with shorter follow-up periods ranging from 2-7 years. On the other hand, in a retrospective cross-sectional study, Lokkegaard et al. (25) found that the glomerular filtration rate decreased slightly, but significantly, and it was estimated that not until after 17 years of treatment did the regression line reach the lower confidence limit in the reference material. A longitudinal follow-up study did not support this view, since the decline in glomerular functioning in patients treated with lithium for an average of 20 years was not larger than might be expected from increasing age (26). The present study is weakened by the fact that it only represents data from 10 (19%) of the original sample of 53 patients. After an average of 8 years, 25% of the patients were still on lithium treatment and the drop-out rate was 57%; 19% had never been treated with lithium or no data about lithium were available. However, the drop-out rate was not larger than might be expected from other investigations (10, 27-29). Although it may be argued that the sample is small, it is also unselected, and keeping in mind the long prospective follow-up period with pre-treatment data, our results underline the safety of wellcontrolled long-term lithium treatment. Acknowledgements This study was supported by grants from the Danish Medical Research Council. Statistical consultant: Cand. stat. Peter Allerup.
References 1. BAASTRUP PC, S c ~ o M. u Lithium as a prophylactic agent against recurrent depression and manic-depressive psychopsis. Arch Gen Psychiatry 1967: 16: 162-172. 2. SCHOUM. Lithium treatment: a refresher course. Br J Psychiatry 1986: 149: 541-547. 3. HESTBECH J, HANSENHE, AMDISENA, OLSENS. Renal lesions following long-term treatment with lithium salts. Kidney Int 1977: 12: 205-213. 4. BOTONR, GAVIRIAM, BATTLE,DC. Prevalence, pathogenesis, and treatment of renal dysfunction associated with
chronic lithium therapy. Am J Kidney Dis 1987: 10:329-345. 5. SCHOUM. Effects of long-term lithium treatment on kidney function. An overview. J Psychiatr Res 1988: 22: 287-296. P. Clinically important side effects of long6. VESTERGAARD term lithium treatment: a review. Acta Psychiatr Scand 1983: 67: (suppl 305): 1-36. 7. SMIGAN L, BUCHTG, vON KNORRING L et al. Long-term lithium treatment and renal functions. Neuropsychobiology
1984: 11: 33-38. 8. JENSENSB, RICKERS H. Glomerular filtration rate during lithium-therapy. Acta Psychiatr Scand 1984: 70: 235-238. 9. AMSTERDAM JK, JORKASKY D, POTTERL, Cox M. A prospective study of lithium-induced nephropathy: preliminary results. Psychopharmacol Bull 1985: 21: 81-84. P. Prospective studies on a lith10. SCHOUM, VESTERGAARD ium cohort. 11. Renal function. Water and electrolyte metabolism. Acta Psychiatr Scand 1988: 78: 427-433. 11. VESTERGAARD P, AMDISENA, HANSENHE, SCHOUM. Lithium treatment and kidney function. A survey of 237 patients in long-term treatment. Acta Psychiatr Scand 1979:60:
504-520. 12. TYRERSP, SCHACHT RG, MCCARTHY MJ, MENARD KN, LEONGS, SHOPSIN B. The effect of lithium on renal haemodynamic function. Psycho1 Med 1983: 13: 61-69. 13. JOHNSON GFS, HUNTGE, DUGGINGG, HORVATH JS, TILLER DJ. Renal function and lithium treatment: initial and follow-up tests in manic-depressive patients. J Affective Disord 1984: 6: 249-263. 0,BOLWIG TG, BRUNC, LADEFOGED J, LARSEN 14. HETMAR S, RAFAELSEN OJ. Lithium: long-term effects on the kidney. I. Renal function in retrospect. Acta Psychiatr Scand 1986: 73: 574-581. 15. HULLINRP, COLEYVP, BIRCHNJ, THOMAS TH, MORGAN DB. Renal function after long-term treatment with lithium. Br Med J 1979: 2: 1457-1459. 16. COPPENA,BISHOPME, BAILEYJE, CATTELL WR, PRICE RG. Renal function in lithium and non-lithium treated patients with affective disorders. Acta Psychiatr Scand 1980: 62: 343-355. 17. PLENGEP,MELLERUP ET. Lithium and the kidney: is one daily dose better than two? Compr Psychiatry 1986:27:336342. 18. HETMAR0,BRUN C, CLEMMESEN L, LADEFOGED J, LARSENS, RAFAELSEN OJ. Lithium. Long-term effects on the kidney. 11. Structural changes. J Psychiatr Res 1987:21: 279-288. AJ, WOJCIKJD, FALDWE et al. Effects of 19. GELENBERG lithium on the kidney. Acta Psychiatr Scand 1987:75:29-34. 20. WALKERRG, BENNETTWM, DAVIESBM, KINCAIDSMITHP. Structural and functional effects of long-term lithium therapy. Kidney Int 1982: 12 (suppl 11): S-13-S-15. L, SMIGANL. 21. WAHLINA, BUCHTG, VON KNORRING Kidney function in patients with affective disorders with and without lithium therapy. Int Pharmacopsychiatry 1980: 15:
253-2 59. 22. VESTERGAARD P, AMDISENA. Lithium treatment and kidney function. A follow-up study of 237 patients in long-term treatment. Acta Psychiatr Scand 1981: 63: 333-345. JG, POLAK A. Neuroleptics, lith23. WALLERDG, EDWARDS ium and renal function. Br J Psychiatry 1985: 146: 510-514. 24. HETMAR0,RAFAELSEN OJ. Lithium: long-term effects on the kidney. IV. Renal lithium clearance. Acta Psychiatr Scand 1987: 76: 193-198. 25. LBKKEGAARD H, ANDERSENHF, HENRIKSEN E etal. Renal function in 153 manic-depressive patients treated with lithium for more than five years. Acta Psychiatr Scand 1985: 71: 347-355. 26. HETMAR0,JUULPOVLSENU, LADEFOGED J, BOLWIG TG. Lithium: long-term effects on the kidney. A prospective
59
Povlsen et al. follow-up study ten years after kidney biopsy. Br J Psychiatry 1991: 158: 53-58. 27. FRANK E, PRIENRF, KUPFERDJ, ALBERTS L. Implications of noncompliance on research in affective disorders. Psychopharmacol Bull 1985: 21: 37-42. 28. PAGEC, BENAIMS, LAPPINF. A long-term retrospective
60
follow-up study of patients treated with prophylactic lithium carbonate. Br J Psychiatry 1987: 150: 175-179. 29. MAARBJERG K, ~LAGAARDJ, VESTERGAARD P. Adherence to lithium prophylaxis. I. Clinical predictors and patient’s reasons for nonadherence. Pharmacopsychiatry 1988: 21: 121-125.
-a
Kidney functioninrr during lithium treatment: a prospective study of patien treated with lithium for up to ten years U
..
Povlsen UJ, Hetmar 0, Ladefoged J, Bolwig TG. Kidney functioning during lithium treatment: a prospective study of patients treated with lithium for up to ten years. Acta Psychiatr Scand 1992: 85: 56-60. A cohort of 53 patients with affective disorders who originally carried through renal functional tests before start of prophylactic lithium treatment were followed up prospectively after an average period of 8.5 years (range 7-10 years). Ten patients who had continued lithium treatment were re-examined. In this subgroup, the glomerular function was unaffected by the treatment, whereas the average urine volume increased during lithium treatment (NS). Polyuria and low renal concentrating abilities were also found before start of treatment and these findings underline the importance of access to renal baseline information prior to lithium treatment.
The prophylactic effect of lithium in manic-depressive illness is by now one of the best documented in psychiatric pharmacotherapy (1,2). In clinical practice it was accepted that thirst and polyuria would develop in many patients on lithium, a complication attributed to decreased responsiveness of the renal tubules to antidiuretic hormone. These unwanted effects were regarded as strictly functional and fully reversible and therefore unlikely to be associated with morphological abnormalities. In 1977,however, evidence of a chronic interstitial nephropathy was reported in a small number of patients with lithium intoxication and/or marked polyuria (3). These reports initiated a large number of systematic studies on the renal impact of lithium treatment (4, 5). In general, no significant deterioration in glomerular filtration rate has been shown, whereas a decrease in renal concentrating capacity in a majority of patients on long-term lithium treatment has been reported (6). Most of the clinical studies have been crosssectional and therefore of limited value, since it is impossible to conclude whether the observed values are associated with lithium. Prospective studies providing baseline information on glomerulotubular function before start of treatment and using patients as their own controls during treatment enable definitive identification of a putative lithium-induced renal impairment of a progressive nature. Studies using this method are few in number and generally the observation periods have been short: 1 year (7), 2 years (8), 3 years (9) and 7 years (10). 56
’,
’,
U. J. Povlsen 0. Hetmar J. Ladefoged T. G. Bolwig
’, ’
’
Departments of Psychiatry and Nephrology, Rigshospitalet, University of Copenhagen, Denmark
Key words: lithium prophylaxis; renal functioning; longitudinal study Uffe Juul Povlsen, M.D., Department of Psychiatry, 6223, Rigshospitalet. Blegdamsvej 9, DK-2100 Copenhagen, Denmark Accepted for publication August 9, 1991
This article presents a prospective follow-up study of 53 pre-lithium control patients, some of which have now been in lithium treatment for 10 years, with special emphasis on renal functioning. Material and methods Pre-lithium examination
The original sample was established from September 1977 to October 1980 in the Department of Psychiatry, Rigshospitalet, Copenhagen, Denmark, and consisted of 53 patients with a diagnosis of affective disorders (ICD 296), never treated with lithium but selected because commencement of prophylactic treatment was under consideration. Mean age at the pre-lithium examination was 40 years (range 19-7 1); 33 patients were women, 20 men. None of the patients had a past history of renal disease, cardiovascular disorder or diabetes mellitus. The average number of affective episodes was 7 at the time of the baseline investigation. Two patients had only had manic episodes, 23 patients depression and 28 patients were bipolar. At the time of the pre-lithium examination most of the patients, 38/53, were on additional psychopharmacological treatment, either antidepressants alone or in various combinations with antipsychotic medication. FOIIOW-UP study
From October to December 1987 a follow-up investigation of the original sample was carried out.
Kidneys and lithium Forty-three patients of this sample began lithium treatment and 7 patients never started lithium, partly because of change of diagnosis or because the patients became stable during treatment with tricyclic antidepressants. Three patients moved to other regions and no data about lithium treatment were available. Thirty patients (19 women, 11 men) had stopped their lithium treatment after an average of 2.6 years (range 0.2-8.2). The main reasons for discontinuation of lithium were side effects in 6 patients, insufficient therapeutic effect in 2 patients, a general aversion to lithium in 7 and diagnostic re-evaluation in 5 patients. Another 2 patients stopped lithium in relation to suicidal behavior, and lithium was discontinued in relation to pregnancy in 2 patients. No follow-up data were available on 6 patients. Thirteen patients who had continued lithium treatment were invited to participate in a re-examination of kidney functioning. Ten patients agreed to take part. Informed consent was obtained from all. Exactly the same renal functional tests as in the prelithium examination were performed during a 5-d admission to the Psychochemistry Research Ward, Rigshospitalet, which has metabolic facilities to ensure complete urine collection. Analyses and functional tests
Two clearances were performed: 1. Endogenous creatinine clearance: urine was collected quantitatively for three 24-h periods and creatinine clearance was calculated from the urine and serum creatinine. Median values were used in the statistical analysis. 2. Lithium clearance (CLi): the patients were instructed to empty their bladders at 0800 and to collect all subsequent urine for the next 24 h divided in the following periods: 1) 0800-1500, 2) 1500-2200 and 3) 2200-0800. Blood samples were taken at 0800, 1500 and 2200. CLi was calculated as follows: cu x
v
ACp x time
=
CLi,
where Cu = lithium urine concentration and V = urine volume. A Cp equals the regressed serum lithium level at the midpoint of the period as expressed by the following equation: Cp (start of period) - Cp (end of period) 2.3 x log (Cp (start of period)/Cp (end of period)) The mean lithium clearance of the 3 periods was then calculated considering the length of the period (in hours):
c
.=
7 x CLi(1)
+ 7 x CLi(2) + 10 x
CLi(3))
L1
24 All clearances were expressed as ml/s. Renal concentration capacity was determined by a 26-h water deprivation test. The period was shortened to 8 h if a patient lost more than 3% of body weight during the first 8 h of water deprivation. Serum and urine osmolality was determined by a Knauer Osmometer and expressed as mosmol/kg H,O. Statistical analysis
Nonparametric statistical tests (Mann-Whitney, Wilcoxon’s test) were applied when direct ungrouped observations were compared. For grouped data, ordinary chi-square tests for contingency tables were used or, in case of sparse data, generalized Fisher’s exact test. All statistical tests were two-tailed and evaluated with respect to significance at 5 % . Test results are reported using significance probabilities. Results
All 10 patients (6 women, 4 men) had continued their lithium treatment without known interruptions, and no symptoms of lithium intoxication had occurred. Serum lithium monitoring was performed every third to sixth month. Mean age at the followup investigation was 47 years (range 34-65) and the average duration of lithium treatment was 8 years (range 7-10). At steady-state the serum lithium levels was 0.77mmol/l (range 0.66-0.92) and the average lithium dosage was 23.4 mmo1/24 h (range 1632). All patients were on a single-dose schedule taking either conventional carbonate tablets (7 patients) or a sustained-release lithium citrate preparation (LitarexO, 3 patients). Two patients were treated with lithium only, whereas 5 patients concomitantly received tricyclic antidepressants and 3 patients both antidepressants and antipsychotic preparations. During the follow-up period half of the patients had no admissions to psychiatric hospitals, whereas the other half had a total of 18 admissions (mean 3.6; range 1-6). Serum creatinine increased significantly from 0.087 mmol/l (range 0.07-0.11) at the pre-lithium test to 0.099 mmol/l at retest (range 0.09-0.14; P = 0.02 (Wilcoxon’s test)). One male patient had a serum creatinine value that exceeded the normal range (0.14 mmol/l). In our laboratory the normal range is 0.06-0.13 mmol/l for men and 0.040.1 1 mmol/l for women. Urine volume increased from a mean pre-lithium value of 2053 m1/24 h (range 1328-4100) to 2519 ml/ 57
Povlsen et al. 24 h (range 1630-4620) on lithium maintenance ( P = 0.06 (Wilcoxon’s test)). A marked change was seen in 1 patient, who had an increase in urinary output from 2690 to 4620 m1/24 h, respectively. Another man had a remarkably high urine volume before start of lithium treatment (4100 m1/24 h), but no significant change was seen on lithium. Maximum renal concentrating capacity was determined in 7 patients before lithium treatment (mean 847 mosmol/kg H,O; range 649-989) and in 6 patients during lithium treatment (mean 868 mosmol/ kg H,O; range 675-1090). Only minor changes were found. Two patients had urine osmolalities below 800 mosmol/kg H20. Endogenous creatinine clearance decreased from a pre-lithium value of 1.77 ml/s (range 1.34-2.70) to a lithium value of 1.70 ml/s (range 1.11-2.49) ( P = 0.17 (Wilcoxon’s test)). Two patients on lithium had creatinine clearances below normal range (1.1 1 and 1.27 ml/s, respectively). Renal lithium clearance decreased from 0.46 ml/s (range0.26-0.82) at the first investigation (n = 7) to 0.42ml/s (range 0.30-0.61) at the follow-up ( n = 10) (NS). Discussion
This longitudinal study presents prospective renal functioning tests and retrospective clinical data from a cohort of 53 patients with affective disorders, who were examined about 10 years ago because commencement of lithium treatment was considered. Subsequently, 10 patients out of this cohort were continuously treated with lithium for an average of 8 years (range 7-10). Our study showed no significant impairment of tubular functioning following lithium treatment. Although the average urine volume increased from 2 to 2.5 1/24 h, the difference was not significant. Maximum renal concentrating capacity was almost unchanged during the follow-up period, both in terms of mean values and intraindividual differences. Impairment of renal concentrating capacity has been the most consistent finding in cross-sectional as well as longitudinal studies (1 1-14), but the prevalence and reversibility is still uncertain. In a total of 1105 unselected lithium-treated patients, 54 % had a subnormal concentrating capacity relative to normal ranges (4). However, the impairment of concentrating capacity was reported to be mild or moderate in other studies (15, 16). The impact of lithium on tubular functioning depends on various factors. First, the action of lithium may depend on lithium dosage schedule. Recent studies suggest that renal functioning and structure is less affected in organisms receiving lithium once a day compared with patients given lithium in 2-3 divided daily doses 58
(17, 18). In the present study, all patients had received lithium in a single daily dosage and had followed the same regimen throughout the entire treatment period, which may explain the relatively unaffected tubular functioning. However, the number of patients and the non-allocated design of the study do not allow any definitive conclusion. Second, the impact may depend on lithium dosage. Our clinic, like many other, has gradually adopted lower lithium levels and the serum lithium concentrations used in this study were generally lower than those in our retrospective functional study (14), which may explain the differently affected concentrating capacity. Third, the impairment of concentrating capacity may not be specifically related to lithium, but also to other factors associated with affective illness. Controlled studies have shown that renal concentrating capacity was impaired in both lithium and nonlithium-treated control patients, but the difference was not significant, and all groups had mean values below 800mosmol/kg H 2 0 (15, 16, 19). This is in agreement with a renal biopsy study by Walker et al. (20), who compared renal biopsies from 47 lithiumtreated patients with specimens from 32 patients with affective disorders who had never received lithium. No difference in the percentage of interstitial fibrosis between the 2 patients groups was found, which questions the relationship between lithium and structural renal changes, but might explain the reduced concentrating capacity found in other patients not treated with lithium. However, other studies have reported a significantly lower maximum renal concentrating capacity in lithium-treated patients than in affectively ill control patients receiving other drugs (12, 18, 21-23). In our study, 2 patients had subnormal concentrating capacity. One patient was a 38-year-old male who was permanently in treatment with 150-200 mg imipramine per day and had complaints of thirst and dry mouth. The reduction in concentrating capacity at the initial investigation corresponded to polyuria (4100 mo1/24 h), which did not increase after 9 years on lithium (3800 m1/24 h). He was unable to carry through the fluid deprivation test because of dizziness and nausea. Another patient had developed polyuria after start of lithium treatment and was also unable to complete the thirst test because of weight loss. About 6-7 years previous to the re-examination, he had developed arterial hypertension and was periodically in treatment with diuretics, but not at the follow-up investigation, and his polyuria is probably unrelated to lithium. The importance of access to renal baseline information prior to lithium use is underlined by these cases. The study revealed a significant increase in mean serum creatinine from 0.087 to 0.099 mmol/l, but
Kidneys and lithium only a single value was marginally increased. However, determination of serum creatinine is a rather inaccurate measure for glomerular functioning and the decrease in mean endogenous creatinine clearance from 1.77 to 1.70 mljs was not greater than might be expected from increasing age (10 ml/min/ decade (24)). Two patients had clearance values below 1.30 ml/s, but both had normal renal lithium clearances. During lithium treatment all 10 patients had lithium clearances within normal range (0.170.67 ml/s). Our study speaks against any significant deterioration in glomerular functioning during lithium treatment for an average of 8 years, which is in agreement with other prospective studies (8, 10) with shorter follow-up periods ranging from 2-7 years. On the other hand, in a retrospective cross-sectional study, Lokkegaard et al. (25) found that the glomerular filtration rate decreased slightly, but significantly, and it was estimated that not until after 17 years of treatment did the regression line reach the lower confidence limit in the reference material. A longitudinal follow-up study did not support this view, since the decline in glomerular functioning in patients treated with lithium for an average of 20 years was not larger than might be expected from increasing age (26). The present study is weakened by the fact that it only represents data from 10 (19%) of the original sample of 53 patients. After an average of 8 years, 25% of the patients were still on lithium treatment and the drop-out rate was 57%; 19% had never been treated with lithium or no data about lithium were available. However, the drop-out rate was not larger than might be expected from other investigations (10, 27-29). Although it may be argued that the sample is small, it is also unselected, and keeping in mind the long prospective follow-up period with pre-treatment data, our results underline the safety of wellcontrolled long-term lithium treatment. Acknowledgements This study was supported by grants from the Danish Medical Research Council. Statistical consultant: Cand. stat. Peter Allerup.
References 1. BAASTRUP PC, S c ~ o M. u Lithium as a prophylactic agent against recurrent depression and manic-depressive psychopsis. Arch Gen Psychiatry 1967: 16: 162-172. 2. SCHOUM. Lithium treatment: a refresher course. Br J Psychiatry 1986: 149: 541-547. 3. HESTBECH J, HANSENHE, AMDISENA, OLSENS. Renal lesions following long-term treatment with lithium salts. Kidney Int 1977: 12: 205-213. 4. BOTONR, GAVIRIAM, BATTLE,DC. Prevalence, pathogenesis, and treatment of renal dysfunction associated with
chronic lithium therapy. Am J Kidney Dis 1987: 10:329-345. 5. SCHOUM. Effects of long-term lithium treatment on kidney function. An overview. J Psychiatr Res 1988: 22: 287-296. P. Clinically important side effects of long6. VESTERGAARD term lithium treatment: a review. Acta Psychiatr Scand 1983: 67: (suppl 305): 1-36. 7. SMIGAN L, BUCHTG, vON KNORRING L et al. Long-term lithium treatment and renal functions. Neuropsychobiology
1984: 11: 33-38. 8. JENSENSB, RICKERS H. Glomerular filtration rate during lithium-therapy. Acta Psychiatr Scand 1984: 70: 235-238. 9. AMSTERDAM JK, JORKASKY D, POTTERL, Cox M. A prospective study of lithium-induced nephropathy: preliminary results. Psychopharmacol Bull 1985: 21: 81-84. P. Prospective studies on a lith10. SCHOUM, VESTERGAARD ium cohort. 11. Renal function. Water and electrolyte metabolism. Acta Psychiatr Scand 1988: 78: 427-433. 11. VESTERGAARD P, AMDISENA, HANSENHE, SCHOUM. Lithium treatment and kidney function. A survey of 237 patients in long-term treatment. Acta Psychiatr Scand 1979:60:
504-520. 12. TYRERSP, SCHACHT RG, MCCARTHY MJ, MENARD KN, LEONGS, SHOPSIN B. The effect of lithium on renal haemodynamic function. Psycho1 Med 1983: 13: 61-69. 13. JOHNSON GFS, HUNTGE, DUGGINGG, HORVATH JS, TILLER DJ. Renal function and lithium treatment: initial and follow-up tests in manic-depressive patients. J Affective Disord 1984: 6: 249-263. 0,BOLWIG TG, BRUNC, LADEFOGED J, LARSEN 14. HETMAR S, RAFAELSEN OJ. Lithium: long-term effects on the kidney. I. Renal function in retrospect. Acta Psychiatr Scand 1986: 73: 574-581. 15. HULLINRP, COLEYVP, BIRCHNJ, THOMAS TH, MORGAN DB. Renal function after long-term treatment with lithium. Br Med J 1979: 2: 1457-1459. 16. COPPENA,BISHOPME, BAILEYJE, CATTELL WR, PRICE RG. Renal function in lithium and non-lithium treated patients with affective disorders. Acta Psychiatr Scand 1980: 62: 343-355. 17. PLENGEP,MELLERUP ET. Lithium and the kidney: is one daily dose better than two? Compr Psychiatry 1986:27:336342. 18. HETMAR0,BRUN C, CLEMMESEN L, LADEFOGED J, LARSENS, RAFAELSEN OJ. Lithium. Long-term effects on the kidney. 11. Structural changes. J Psychiatr Res 1987:21: 279-288. AJ, WOJCIKJD, FALDWE et al. Effects of 19. GELENBERG lithium on the kidney. Acta Psychiatr Scand 1987:75:29-34. 20. WALKERRG, BENNETTWM, DAVIESBM, KINCAIDSMITHP. Structural and functional effects of long-term lithium therapy. Kidney Int 1982: 12 (suppl 11): S-13-S-15. L, SMIGANL. 21. WAHLINA, BUCHTG, VON KNORRING Kidney function in patients with affective disorders with and without lithium therapy. Int Pharmacopsychiatry 1980: 15:
253-2 59. 22. VESTERGAARD P, AMDISENA. Lithium treatment and kidney function. A follow-up study of 237 patients in long-term treatment. Acta Psychiatr Scand 1981: 63: 333-345. JG, POLAK A. Neuroleptics, lith23. WALLERDG, EDWARDS ium and renal function. Br J Psychiatry 1985: 146: 510-514. 24. HETMAR0,RAFAELSEN OJ. Lithium: long-term effects on the kidney. IV. Renal lithium clearance. Acta Psychiatr Scand 1987: 76: 193-198. 25. LBKKEGAARD H, ANDERSENHF, HENRIKSEN E etal. Renal function in 153 manic-depressive patients treated with lithium for more than five years. Acta Psychiatr Scand 1985: 71: 347-355. 26. HETMAR0,JUULPOVLSENU, LADEFOGED J, BOLWIG TG. Lithium: long-term effects on the kidney. A prospective
59
Povlsen et al. follow-up study ten years after kidney biopsy. Br J Psychiatry 1991: 158: 53-58. 27. FRANK E, PRIENRF, KUPFERDJ, ALBERTS L. Implications of noncompliance on research in affective disorders. Psychopharmacol Bull 1985: 21: 37-42. 28. PAGEC, BENAIMS, LAPPINF. A long-term retrospective
60
follow-up study of patients treated with prophylactic lithium carbonate. Br J Psychiatry 1987: 150: 175-179. 29. MAARBJERG K, ~LAGAARDJ, VESTERGAARD P. Adherence to lithium prophylaxis. I. Clinical predictors and patient’s reasons for nonadherence. Pharmacopsychiatry 1988: 21: 121-125.
