Lithium and long‐term renal effects: A complex clinical concern
Michael Gitlin
Abstract
Potential nephrotoxicity from long-term lithium use has been well documented for many decades, with the first paper demonstrating structural renal damage, primarily in the form of interstitial nephritis (with scarring of the interstitium, tubular destruction and relative preservation of glomeruli), published in 1977.1 The trajectory of renal function in patients who have had lithium treatment discontinued due to progressive renal impairment (previously measured by serum creatinine, more recently measured by eGFR [estimated glomerular filtration rate]) is still not clear. Studies have shown that, after lithium discontinuation, renal function either stabilizes or improves in many patients while other patients, especially those with worse renal function at the time of lithium discontinuation, show further deterioration in renal function.2 Among the variables that may explain these discrepant results are: (1) the effect of comorbid medical disorders that independently adversely affect renal function such as diabetes or hypertension; (2) the extent of renal damage at the time of lithium discontinuation. As an example, in one recent study, individuals most likely to show progressive deterioration of renal function after lithium discontinuation were those whose eGFR was 32 mL/min or less.2 This finding is consistent with previous studies showing similar results. (3) A final variable, which may be the most important of all, is the length of follow-up after lithium discontinuation. Many studies in this area have followed patients for 1–5 years. However, renal function normally and inevitably deteriorates with age and it may take decades for mild to moderate chronic kidney disease (CKD) (e.g. stage 3, with an eGFR<60) to progress to end-stage renal disease (ESRD). Beyond the frustration of conflicting data, the key issue is that of balancing the risk of treating vs. the risk of not treating, that is removing the treatment that is beneficial. For lithium, the risk of continuing lithium treatment in the face of progressive deterioration in renal function is that of inexorable renal damage. The risk of not treating reflects the frequent observation that, for many patients, treatment with lithium can be either extraordinarily effective or even life-saving given the morbidity of recurrent bipolar episodes. Consistent with this, one recent study demonstrated that patients who discontinued lithium due to CKD stage 3 had more mood episodes, and more psychotropic medication trials compared to those who continued lithium treatment.3 The UCLA Mood Disorders Clinic has been providing longitudinal care to patients with unipolar and bipolar disorder for 45 years. Therefore, we have followed a number of patients for many decades. To illustrate the importance and effect of long-term observation, four brief clinical vignettes of patients with bipolar I disorder treated with lithium are presented, demonstrating both the potential for progression to ESRD in three patients, the toxic effects of dialysis in one of these patients and mood destabilization from discontinuing lithium in another patient. Mr. A, previously reported on 30 years ago as Mr. C in Gitlin, 1993,4 with bipolar I disorder, was treated with lithium. He developed a rising serum creatinine, which was 2.1 mg/100 mL at the time of lithium discontinuation after 12 years of treatment. After lithium discontinuation, he developed a treatment refractory depression. His renal function deteriorated thereafter and he was eventually placed on dialysis treatment. When it was clear that he was inevitably progressing to ESRD and dialysis or renal transplantation, his lithium was restarted with resolution of his depression. However, while on haemodialysis, he continued to have recurrent mood episodes despite the addition of other mood stabilizers to his lithium treatment. The patient refused renal transplantation due to his fear of the requisite corticosteroid treatment post-transplant and its potential to precipitate another manic episode. (He had experienced a hospitalized manic episode in the past associated with corticosteroid use). He eventually developed dialysis-related dementia and died at age 64 of an arrhythmia due to metabolic imbalance related to his dialysis treatment. Ms. B (also previously reported on in Gitlin, 19934 after 6 years of lithium treatment developed a serum creatinine of 2.5 mg/100 mL. After valproate plus bupropion were added, lithium was tapered and discontinued. Over the next 5 years, her serum creatinine decreased to 1.7 mg/100 mL. She did very well for decades on valproate plus bupropion. However, over the next 30+ years, off lithium, her renal function slowly and progressively deteriorated to a current eGFR = 13, meeting diagnostic criteria for ESRD (eGFR<15). Now aged 65 years old, she is preparing for dialysis or renal transplantation. Ms. C, now 51 years old, took lithium with excellent effect for 6 years. In 2000, her lithium was discontinued due to a serum creatinine of 1.8–2.0 ng/100 mL. After 2 years of mood instability, she was eventually well-stabilized on oxcarbazepine plus lamotrigine. Over the next 23 years, her renal function gradually deteriorated. Currently, her eGFR <15, meeting criteria for ESRD and she is preparing for renal transplantation. Ms. D, after very effective long-term treatment with lithium, was evaluated by a nephrologist who recommended discontinuing lithium because of a progressive decrease in her eGFR. Lithium was discontinued when her eGFR was 38 (CKD stage 3b). Despite many other therapies, including other mood stabilizers and ECT, she died by suicide within 1 year of discontinuing lithium. These four cases illustrate a set of difficult clinical decisions regarding long-term lithium use. The absolute risk for ESRD in lithium-treated is very low, even if the relative risk is substantial. Recent estimates of ESRD associated with lithium range between 0.2 and 0.7%, which is an almost eightfold risk compared to the general population.5 But, clinically, how does one weigh the relative risk of end-stage renal disease compared to the potential for a less well-treated bipolar I disorder? Ms. B and Ms. C were both successfully treated with other mood stabilizers after lithium discontinuation. Ms. D was clearly not. Mr. A continued to have recurrent mood cycles both on and off lithium. Despite the cycling while on lithium, he felt that his mood swings, while present were milder when taking lithium. Additionally, how does one accurately and succinctly describe the risk/benefit issues about lithium with bipolar patients as part of informed consent? Does one acknowledge the rare but potentially increased risk for ESRD decades in the future at the time of initiating lithium treatment? Does one discuss this only if and at the time of a progressive decline in eGFR? Finally, at what level of renal function should lithium discontinuation be considered and discussed? The literature suggests that eGFR = 40 mL/min or less is associated with greater risk of further renal function deterioration. Should the discussion occur then or earlier, if/when the patient develops CKD stage 3 (eGFR <60 mL/min)? As a field, we must grapple with these thorny dilemmas, which have no clear answers but real clinical consequences. Most importantly, however, we should at least remind ourselves that short-term (measured in a few years) observations may be reassuring but may underestimate very long-term outcomes that are seen only after decades of observation. Michael Gitlin has conflicts of interest to declare. Data sharing is not applicable to this article as no datasets were generated or analysed during the current study.