Wednesday, 28.10.2020

Janos Rado. Renal toxicity of lithium in historical perspective with special reference to nephrogenic diabetes insipidus and its treatment.

Janusz Rybakowski’s commentary


          The paper written by Janos Radó provides a detailed description of one of the frequent renal side-effects of lithium: an impairment of renal concentrating ability which, in rare cases, can have its apogeum in lithium-induced nephrogenic diabetes insipidus. As to diabetes insipidus, the author discusses the available treatments of this condition pointing to the clever use of modern antidiuretic interventions. This may provide clinicians employing lithium in patients with mood disorders and encountering such a side effect, a variety of options for its management.

          However, from nearly a half-century perspective of the practice of lithium treatment, I can voice an opinion that lithium-induced impairment of renal concentrating ability, leading infrequently to nephrogenic diabetes insipidus, may not be a major kidney problem connected with the long-term lithium therapy. This side-effect of lithium can be observed as early as after several weeks of lithium therapy and, in most cases, disappears completely after lithium discontinuation; it can also be effectively treated according to Dr. Rado's guidelines. During long-term lithium treatment, many patients present some degree of impairment of renal concentrating ability, however, in most cases it does not have significant clinical importance and does not lead to lithium discontinuation. The most important kidney side-effect is lithium nephropathy, developing mostly after 10 or more years of lithium treatment and, in some cases, can result in renal failure and make a real case for termination of lithium therapy. In good responders to long-term lithium, it may have a detrimental effect to the illness since a replacement of lithium with another mood stabilizer is usually not so effective.

          My experience with lithium therapy dates back to 1970 when I started such treatment at the Department of Psychiatry, Medical Academy, Poznan, Poland. Two years later I described, first in Polish medical literature, a case of lithium-induced diabetes insipidus. This side effect occurred after several weeks of lithium therapy and disappeared following lithium discontinuation (Rybakowski and Daszynska 1972).

          In recent years our group has performed a number of studies on kidney function in long-term lithium-treated patients. In the study published in 2012, 80 patients with a bipolar mood disorder (26 male, 54 female), aged 60 ± 11 years, receiving lithium for 5-38 (16 ± 9) years, were investigated. Decreased estimated glomerular filtration rate (eGFR) values <60 ml/min/1.73/m² were found in 23% of patients, significantly more frequently in men that in women (38% vs. 16%). Specific gravity of the urine, equal to or below 1.005, was recorded in 21% of men and 14% of women (Rybakowski, Abramowicz, Drogowska et al. 2012).

          Since the inhibition caused by lithium of the glucogen synthase kinase-3beta (GSK-3β) makes it the main mechanism of lithium action, we were interested whether the functional -50 C/T polymorphism of the GSK-3β gene could be associated with kidney function in 78 long-term lithium-treated bipolar patients. We found such an association with a lithium effect on urine concentrating capacity. Patients homozygous for C allele had significantly higher urine specific gravities (1.019 ± 0.008) compared to the remaining genotypes (1.013 ± 0.007) (p = 0.035), with no influence attributed to the duration of lithium treatment. Other parameters of kidney function (serum creatinine, eGFR, serum NGAL and urinary β2-MG levels) were not different between genotypes (Rybakowski, Abramowicz, Szczepankiewicz et al. 2013).

          As previously mentioned, the main reasons for lithium discontinuation in long-term lithium-treated patients are the symptoms of lithium-induced nephropathy. However, such a discontinuation, especially in “excellent lithium responders” (ELR), is associated with a high risk of relapse and a treatment-resistant course. We assessed kidney function during a five-year follow-up in the ERL with the glomerular filtration rate (GFR)< 50 ml/min/1.73 m2. Three males and one female were included. At the beginning, their age was 61 ± 0.8 years and duration of lithium treatment was 27 ± 9 years. Kidney parameters (serum creatinine, GFR and urine specific gravity) were assessed at least three times during the five-year follow-up period. In three patients having the initial GRF between 47–48 ml/min/1.73 m2, the kidney parameters did not show significant changes and the patients continued lithium treatment. The patient with the lowest GFR (32 ml/min/1.73 m2) had a 14% decrease in GFR and a 10% increase in serum creatinine. However, urinary specific gravity increased during this time from 1.003 to 1.007. In this patient, the dose of lithium was decreased by one-third and he was placed under strict nephrological observation. Therefore, based on the results and in the ELR with the GFR not much lower than 50 ml/min/1.73 m2, we suggest continuing lithium with a yearly check on kidney parameters. In the ELR with a much lower GFR, a reduction of lithium dose and nephrological observation along with more frequent monitoring would be recommended (Abramowicz, Permoda-Osip, Nowak et al. 2017).

          We also described five patients (two men and three women, aged 64-79 years) with ultra-long-term lithium treatment (40-45 years) and good response to such treatment. Their serum lithium level was maintained within the range of 0.60-0.65 mmol/l, except for one male, having 0.7-0.8 mmol/l. One man had stage 3 chronic kidney disease and the other stage 2/3 chronic kidney disease. All three women had asymptomatic stage 2 chronic kidney disease. However, no progression has been observed within the last five years. The urine specific gravity in all patients was above 1.005. In all patients the cognition and professional activity were at the level of healthy subjects with comparable age and years of education. Their functioning in family and social roles was good. The beginning of lithium prophylaxis had usually been made within the first three years of the illness. Therefore, we could conclude that in patients with favorable response to lithium, such a longitudinal administration of the drug can produce satisfactory performance in vocational and psychosocial areas and the management of potential adverse effects can be adequate (Permoda-Osip, Abramowicz, Kraszewska et al. 2016).

          In conclusion, from a long-term lithium administration perspective, the issue of lithium-induced diabetes insipidus is much less important than lithium-induced nephropathy. However, Dr. Radó should be congratulated for his excellent review of treatment possibilities for this lithium-induced side effect. In my opinion, the extensive therapeutic experience of Dr. Radó with lithium-induced diabetes insipidus deserves an updating publication in a regular bipolar disorder journal and I would encourage him to submit such a paper to the International Journal of Bipolar Disorders.



Abramowicz A, Permoda-Osip A, Nowak B, Olejniczak P, Rybakowski JK. Five-year observation of chronic renal insufficiency during lithium treatment. A case study of four patients. Pharmacother Psychiatry Neurol 2017; 33: 169-79.

Permoda-Osip A, Abramowicz M, Kraszewska A, Suwalska A, Chlopocka-Wozniak M, Rybakowski JK. Kidney, thyroid and other organ functions after 40 years or more of lithium therapy: a case series of five patients. Ther Adv Psychopharmacol 2016; 6: 277-82.

Rybakowski J, Daszyńska M. Case of diabetes insipidus in the course of treatment with lithium carbonate (article in Polish). Pol Tyg Lek 1972; 25: 1527-8.

Rybakowski JK, Abramowicz M, Drogowska J, Chłopocka-Woźniak M, Michalak M, Czekalski S. Screening for the markers of kidney damage in men and women on long-term lithium treatment. Med. Sci Monit 2012; 18: CR656-60.

Rybakowski JK, Abramowicz M, Szczepankiewicz A, Michalak M, Hauser J, Czekalski S. The association of glycogen synthase kinase-3beta (GSK-3β) gene polymorphism with kidney function in long-term lithium-treated bipolar patients. Int J Bipolar Disord 2013; 1: 8.

June 20, 2019