Hans Bendz

Renal failure occurs in chronic lithium treatment but is uncommon.

We sought to establish the prevalence of lithium-induced end-stage renal disease in two regions of Sweden with 2.7 million inhabitants corresponding to about 30% of the Swedish population. Eighteen patients with lithium-induced end-stage renal disease were identified among the 3369 patients in the general lithium-treated population, representing a sixfold increase in prevalence compared with the general population for renal replacement therapy. All lithium-treated patients were older than 46 years at end-stage renal disease with a mean lithium treatment time of 23 years with ten patients having discontinued lithium treatment an average of 10 years before the start of renal replacement therapy. The prevalence of chronic kidney disease (defined as plasma creatinine over 150 micromol/l) in the general lithium-treated population was about 1.2% (excluding patients on renal replacement therapy). Compared with lithium-treated patients without renal failure, those with chronic kidney disease were older and most were men but, as groups, their mean serum lithium levels and psychiatric diagnoses did not differ. We found that end-stage renal disease is an uncommon but not rare consequence of long-term lithium treatment and is more prevalent than previously thought. Time on lithium was the only identified risk factor in this study, suggesting that regular monitoring of renal function in these patients is mandatory.

Drug-induced diabetes insipidus: incidence, prevention and management.

Drug-induced diabetes insipidus is always of the nephrogenic type, i.e. unre-sponsiveness of the kidneys to the action of antidiuretic hormone. This condition is easily diagnosed by measuring urinary concentrating capacity during a thirst test (e.g. 12 hours of water deprivation) or by administration of a modified anti-diuretic hormone, desmopressin, to demonstrate the renal unresponsiveness. Drug-induced nephrogenic diabetes insipidus is not a common disorder except in patients receiving treatment with lithium salts for affective disorders where it may affect about 10% of patients treated long term (15 years). Drug-induced nephrogenic diabetes insipidus caused by other drugs usually occurs in critically ill patients in intensive care units receiving a multitude of drugs dominated by antimicrobials and cytostatics. A search of the World Health Organization’s adverse effect database revealed 359 reports of drug-induced diabetes insipidus. Lithium was the most common cause (159 reports) followed by foscarnet (15) and clozapine (10).Treatment is symptomatic in most patients and the offending drug should be stopped. If urine volumes exceed 4 L/day, treatment with thiazides and amiloride has been advocated, and nonsteroidal anti-inflammatory drugs, such as indometh-acin, may be tried in severe cases. Prevention of lithium-induced nephrogenic diabetes insipidus is an important aspect of the treatment of affective disorders.In patients treated long term it appears to be only partly reversible upon lithium discontinuation. Close monitoring of the treatment aiming at 12-hour trough value of 0.4 to 0.6 mmol/L is recommended. Yearly measurement of the urinary volume/day is effective in making both the patient and the physician aware of the development of the drug-induced nephrogenic diabetes insipidus. The condition is a serious adverse effect because of the risk of developing dehydration and aggravation of drug intoxications.

A historical cohort study of kidney damage in long-term lithium patients: continued surveillance needed.

BACKGROUND Insufficient knowledge on the longitudinal fate of renal function in lithium patients incited this retrospective study of 149 patients. METHOD Medical record review of a lithium cohort (N = 149), 8--12 years after an initial renal function study. RESULTS Twenty-one patients had died, one from uremia probably not caused by lithium, and 42 had discontinued lithium. Reduced urinary concentrating capacity (Umax) or glomerular filtration rate (GFR) was not more frequent among deceased or off-lithium patients than among the 86 patients who were on lithium at follow-up. In 63 of the latter patients, Umax had been re-examined after the initial study, and GFR in 29 patients. Reduced Umax and GFR had become twice as common, and average Umax and GFR had decreased significantly. The reduction of GFR was associated with lithium treatment duration and age, and reduced Umax with treatment duration only. CONCLUSIONS Reduced renal function is not a major cause of treatment discontinuation but becomes increasingly common with treatment duration.Limitations. Missing data rendered the interpretation difficult in some respects. Clinical relevance. The increased proportion of patients with reduced GFR and Umax with time implies an increased risk of potentially lethal dehydration and lithium intoxication. Continued surveillance of urinary output and GFR is therefore necessary.

Lamotrigine versus lithium as maintenance treatment in bipolar I disorder: an open, randomized effectiveness study mimicking clinical practice. The 6th trial of the Danish University Antidepressant Group (DUAG-6)

OBJECTIVES In industry-generated pivotal studies, lamotrigine has been found to be superior to placebo and comparable to lithium in the maintenance treatment of bipolar I disorder. Here, we directly compared lamotrigine to lithium under conditions similar to clinical routine conditions. METHODS Adult bipolar I disorder patients with at least two episodes within the last five years and an index episode requiring treatment were randomized to lithium (n = 78; doses adjusted to obtain serum levels of 0.5-1.0 mmol/L) or to lamotrigine (n = 77; up-titrated to 400 mg/day) as maintenance treatments. Randomization took place when clinically appropriate, and comedication was allowed within the first six months after randomization. The patients were enrolled from March 2001 to December 2005, and observations were censored December 2006, allowing a subgroup of patients to be followed for more than five years. The primary outcome measure was time to predefined endpoints indicating insufficient maintenance treatment, and the major secondary outcome measure was time to any study endpoint. Data were analyzed primarily by Cox proportional regression models. RESULTS For the primary outcome measure, the crude Hazard Rate Ratio (HRR) (lamotrigine relative to lithium) was 0.92 [95% confidence interval (CI): 0.60-1.40]. When the primary endpoints were broken down by polarity, the HRRs (lamotrigine relative to lithium) for mania and depression were, respectively, 1.91 (95% CI: 0.73-5.04) and 0.69 (95% CI: 0.41-1.22). There was no between-group difference in terms of staying in study [HRR: 0.85 (95% CI: 0.61-1.19)]. Most treatment failures occurred within the first 1.5 years of treatment, and, among patients followed for at least five years, practically no patients were maintained successfully on monotherapy with either of the drugs. The lithium-treated patients reported diarrhea, tremor, polyuria, and thirst more frequently. Two cases, probably lamotrigine-related, of benign rash occurred. CONCLUSIONS No differences in maintenance effectiveness between lithium and lamotrigine could be demonstrated. Lamotrigine was better tolerated than lithium, but apparently this did not influence the outcome.

The impact of modern treatment principles may have eliminated lithium-induced renal failure

We have previously shown that lithium can cause end-stage renal disease (ESRD): however, this serious side-effect of lithium in prophylactic treatment of mood disorders may reflect the treatment regime of the 1960s and 1970s. Today’s modern treatment routines, intended to reduce or eliminate lithium-induced ESRD (Li-ESRD), were introduced in Sweden in the early 1980s. The aim of the present study was to test the hypothesis that these routines have eliminated the risk of Li-ESRD. We used the Swedish Renal Registry to identify patients on renal replacement therapy (RRT), treated with dialysis or renal transplantation, with suspected Li-ESRD in two regions of Sweden with altogether about three million inhabitants. We reviewed their medical records to verify the exposure to lithium treatment, the diagnosis of Li-ESRD and the date of starting the lithium treatment. We found 32 RRT patients in whom lithium treatment was the sole or main contributing cause of ESRD. The starting year of their lithium treatment was between 1965–1980 in all patients. No patient started lithium treatment later than 1980. Modern lithium treatment may have eliminated the risk of Li-ESRD. Our findings support the continued use of lithium as a safe drug for the long-term treatment of mood disorders.

End-stage renal disease associated with prophylactic lithium treatment.

The primary aim of this study was to estimate the prevalence of lithium associated end-stage renal disease (ESRD) and to compare the relative risk of ESRD in lithium users versus non-lithium users. Second, the role of lithium in the pathogenesis of ESRD was evaluated. We used the Swedish Renal Registry to search for lithium-treated patients with ESRD among 2644 patients with chronic renal replacement therapy (RRT)-either dialysis or transplantation, within two defined geographical areas in Sweden with 2.8 million inhabitants. The prevalence date was December 31, 2010. We found 30 ESRD patients with a history of lithium treatment. ESRD with RRT was significantly more prevalent among lithium users than among non-lithium users (p<0.001). The prevalence of ESRD with RRT in the lithium user population was 15.0‰ (95% CI 9.7-20.3), and close to two percent of the RRT population were lithium users. The relative risk of ESRD with RRT in the lithium user population compared with the general population was 7.8 (95% CI 5.4-11.1). Out of those 30 patients, lithium use was classified, based on chart reviews, as being the sole (n=14) or main (n=10) cause of ESRD in 24 cases. Their mean age at the start of RRT was 66 years (46-82), their mean time on lithium 27 years (12-39), and 22 of them had been on lithium for 15 years or more. We conclude that lithium-associated ESRD is an uncommon but not rare complication of lithium treatment.

Effects of 10 to 30 years of lithium treatment on kidney function.

Long-term lithium treatment is associated with end-stage renal disease, but there is little evidence of a clinically significant reduction in renal function in most patients. We previously found that 1.5% of people who took lithium from the 1960s and 1970s developed end-stage renal disease; however, none of the patients who started after 1980 had end-stage renal disease. Here we aimed to study the prevalence and extent of kidney damage during the course of long-term lithium treatment since 1980. We retrieved serum lithium and creatinine levels from 4879 patients examined between 1 January 1981 and 31 December 2010. Only patients who started their lithium treatment during the study period and had at least 10 years of cumulative treatment were included. The study group comprised 630 adult patients (402 women and 228 men) with normal creatinine levels at the start of lithium treatment. There was a yearly increase in median serum creatinine levels already from the first year of treatment. About one-third of the patients who had taken lithium for 10–29 years had evidence of chronic renal failure but only 5% were in the severe or very severe category. The results indicate that a substantial proportion of adult patients who are treated with lithium for more than a decade develop signs of renal functional impairment, also when treated according to modern therapeutic principles. Our results emphasise that lithium treatment requires continuous monitoring of kidney function.

A comparison of plasma cystatin C and plasma creatinine for the screening of renal function in lithium-treated patients.

BACKGROUND Renal insufficiency is a serious complication of lithium treatment. Therefore, regular monitoring of plasma (P) creatinine is always part of lithium treatment safety routines. Recently P-cystatin C-estimated glomerular filtration rate (cystatin C-eGFR) had been launched as a preferable alternative to P-creatinine. AIMS To find out which of the two alternatives to prefer in the safety routines for lithium-treated patients. MATERIAL All 201 patients on lithium treatment at the Department of Psychiatry in Lund, Sweden. METHODS During 14 months P-cystatin C was included in the safety routines besides routine P-creatinine every 4 months. At the end of the study period, 182 patients were eligible for analysis. With iohexol clearance as reference for GFR (performed in 111/182 patients) we calculated positive and negative predictive values (PPV, NPV) for P-creatinine and for creatinine-eGFR and cystatin C-eGFR, obtained by prediction equations. We also calculated the agreement between the measures of GFR (including repeatability). RESULTS PPV for cystatin C-eGFR (65%) was better than for creatinine-eGFR (48%). Combining the two resulted in a PPV of 56% and marginally increased NPV to 95%. The average of cystatin C-eGFR and creatinine-eGFR yielded PPV 67% and NPV 92%. The agreement between creatinine-eGFR and GFR was better than the agreement between cystatin C-eGFR and GFR, but both were clinically unacceptable. The repeatability of P-creatinine was acceptable for psychiatric purposes. The repeatability of cystatin C-eGFR was inferior to that of P-creatinine. CONCLUSION Our results do not justify replacing P-creatinine by cystatin C-eGFR in the lithium treatment safety routines.