Demystifying Lithium Therapy—A Primer for Clinicians: Renal Issues, Part 1

CATEGORY 1 CME

Premiere Date: December 20, 2024

Expiration Date: June 20, 2026

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To inform readers of the recent developments with lithium as they relate to renal issues.

LEARNING OBJECTIVES

1. Educate clinicians about recent advances in the understanding of lithium-related renal dysfunction and practices that mitigate lithium’s renal impact.

2. Describe how lithium’s accumulation in collecting duct principal cells is the cause of polyuria, and describe methods to track this complaint and treat it with the epithelial sodium channel–antagonist amiloride.

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This accredited continuing education (CE) activity is intended for psychiatrists, psychologists, primary care physicians, physician assistants, nurse practitioners, and other health care professionals who seek to improve their care for patients with mental health disorders.

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(This is the first part of a discussion on lithium. Part 2 can be found here.)

Lithium remains underused for the treatment of patients with a history of mania (eg, schizoaffective disorder, bipolar type, or bipolar I disorder [BD-1]), although it remains the gold therapeutic standard as noted in treatment guidelines published since 2018 (Table 1).^1-3 This pattern of underuse persists despite the reproductive harms associated with valproate exposure in women and men,^4-6 naturalistic data documenting higher rates of postmania treatment failure for second generation antipsychotic (SGA) monotherapies (eg, quetiapine, aripiprazole, olanzapine) compared with lithium monotherapy,⁷ and evidence that use of lithium in older patients with BD-I is neuroprotective. Patients with BD-I have a 3-fold higher risk of dementia than do their peers; however, results of a 2020 meta-analysis indicated that long-term use of lithium in older patients with BD-I reduces future dementia risk by 49%.⁸ Concerns about renal adverse effects (AEs) will necessarily limit lithium use in select patients.⁹ However, these concerns are often generalized, and the risks inflated by erroneous assumptions about lithium’s impact on estimated glomerular filtration rate (eGFR) and lack of knowledge about appropriate monitoring and management of polyuria, the earliest signal of lithium-related renal dysfunction.^10,11

This primer will outline the modern understanding of all patient and medication-related factors that impact the development of chronic kidney disease (CKD) in BD spectrum individuals, detail how to minimize lithium’s contribution to CKD risk through single daily dosing at bedtime (QHS) and use of modest 12-hour maintenance serum levels, and delineate why lithium’s entry into distal collecting duct principal cells via the epithelial sodium channel (ENaC) is the primary cause of renal injury, with its earliest manifestation being the patient complaint of polyuria.^12,13 The profound, yet simple, concept that the pathway to lithium-related CKD is via ENaC makes clear why polyuria monitoring is so vital and why the ENaC blocker amiloride is the ideal means of treating this problem.^14,15

CKD and Bipolar Disorder: It Is the Patients, Not Just the Lithium

Studies of cardiometabolic health among those with serious mental disorders consistently report that cardiovascular (CV) risk factors are overrepresented in this population, but these papers often fail to note that those same CV risks overlap with risk factors for CKD: hypertension, dyslipidemia, metabolic syndrome, and type 2 diabetes mellitus.¹⁶ Adults with bipolar spectrum disorders (primarily BD-I and schizoaffective disorder, bipolar type) have higher rates of obesity and cardiometabolic disorders than the general population and this translates to increased risk for CKD.^17,18 A large study using the Danish health registers found that adults with bipolar spectrum disorders (n=10,591) had 3-fold higher rates of CKD and end-stage renal disease than did their peers, and this was independent of lithium or anticonvulsant mood stabilizer use (Table 2).¹⁶ Some of the renal pathology previously attributable to lithium now is understood to result from confounding bias—the use of lithium in a population with elevated inherent CKD risks. The independent effect of lithium on eGFR, while not absent, is more modest than previously estimated^19,20; however, as will be discussed, lithium’s effect on eGFR is magnified by outdated practices such as multiple daily dosing in adults and persistently high maintenance serum levels.^21,22

Despite use of modest 12-hour maintenance serum levels and single QHS dosing, lithium-treated patients can develop CKD due to medical comorbidities. Nonetheless, when somatic medical burden is modest, even patients with low baseline eGFR can be started on lithium without undue impact on age-related eGFR declines. Evidence for this comes from studies such as a 2021 retrospective analysis of eGFR changes among 83 older Swedish patients who started lithium with low baseline eGFR. After using lithium for 7.9 years, 43 patients (52%) did not progress to lower CKD stages despite a mean (SD) baseline age of 55.5 (16.8) years and a mean (SD) baseline eGFR of 54 (15) mL/min.²⁰ Not surprisingly, the 48% of patients who experienced significant eGFR declines had a greater burden of somatic illness than did those who did not (P < .012) and also had numerically higher rates of diabetes mellitus (23% vs 12%, respectively) and CV disorders (63% vs 42%).²⁰

Given the significant neuroprotective effects of lithium and the inevitable presence of CKD risks in older adults with BD-I (OABD), clinicians should not deprive these patients of lithium therapy; instead, clinicians must become adept in using age-appropriate maintenance levels to limit the risk of renal and central nervous system (CNS) AEs. A Delphi panel of 25 experts in OABD convened in 2019 suggested 12-hour maintenance serum levels of 0.4 to 0.8 mEq/L for patients aged 60 to 79 years and 0.4 to 0.7 mEq/L for those aged at least 80 years.²³ Modest serum levels are recommended due to lower eGFR in that population, and due to age-related changes in blood-brain barrier permeability that can generate higher brain-to-serum lithium ratios over time.^24-26 The serum level that was once therapeutic in a younger patient may result in excessive brain exposure as that same individual ages, and be manifested as complaints about cognition and mood.²⁵ Lower maintenance levels thus benefit the OABD’s kidneys and, in turn, their brain.

Sins of Lithium Prescribing: Multiple Daily Dosing Plus High Serum Levels

Lithium was approved in the United States on April 6, 1970; as with many older medications, its product information has remained largely unchanged.²⁷ Despite decades of evidence that the CNS half-life of lithium ranges from 28 to 48 hours,²⁸ prescribing information continues to recommend that it be administered 2, 3, or even 4 times daily.^27,29 This presents a source of danger for the patient, as multiple daily dosing and maintenance levels exceeding 1.00 mEq/L are associated with a greater risk of renal dysfunction.^21,22 High 12-hour maintenance serum levels, as illustrated in Table 3, relate to the fact that the level obtained in a patient taking lithium twice daily is not the same as a level obtained after a single QHS dose; when administered on a twice-daily schedule, half of the lithium is ingested 24 hours before the morning level is drawn. If the entire dosage intended to be given twice daily is consolidated to a single QHS dose, it results in the repeat level being 28% higher than previously estimated.^30-32

Modern consensus guidelines recommend that maintenance 12-hour serum levels be 0.6 to 0.8 mEq/L for most adults younger than 60 years³³; in no instances should levels exceed 1.00 mEq/L. These recommendations are based on once-daily QHS dosing. Unfortunately, clinicians may misinterpret the level on twice-daily dosing as being mathematically and clinically equivalent to that with QHS dosing. It is not. If a patient is counseled on reasons to consolidate their lithium dosage to a single QHS dose but remains opposed, clinicians can estimate the level that would have been obtained by multiplying the level drawn 12 hours after the nightly dose by 1.28 and then adjusting the dose accordingly.³⁴ Extended-release (ER) preparations should also be dosed once daily at bedtime; the 12-hour serum levels obtained with ER formulations are comparable to those of standard lithium formulations despite the slightly longer time to peak drug concentration (range, 3-6 vs 1-3 hours, respectively).³⁴

The association of multiple daily dosing and increased rates of renal dysfunction has been known for over 40 years,³⁵ but the evidence was not of the highest quality until a paper published in 2016 cemented the concept that once-daily dosing is renoprotective.²¹ The authors performed a case-control study of lithium treated adults in a large New England health care system in which they matched 1445 individuals with renal insufficiency (RI) 1:3 with 4306 patients without RI. In the fully adjusted model, once-daily dosing was associated with a 20% lower risk of renal insufficiency (OR, 0.80; 95% CI, 0.69-0.93; P = .003). Moreover, increased risk of RI was not seen for ER formulations when that variable was analyzed independently.

These findings, however, only apply to the treatment of adults. Children and preteen adolescents have markedly higher lithium clearance than do adults. In young patients, lithium is commonly dosed 3 times daily (mean total daily dose, 25 mg/kg).³⁶ As these individuals approach maturity, lithium can slowly be transitioned to once-daily QHS dosing. One other useful finding from the case-control study was that even 1 high outpatient level can increase the risk of RI risk; any level exceeding 1.2 mEq/L increased the risk of RI by 72% (OR, 1.72; 95% CI 1.38-2.14).²¹

ENaC: What It Means, and Why It Relates to Polyuria

Lithium is filtered and reabsorbed in the glomerulus and proximal tubules in a manner equivalent to that of sodium; it is in the distal collecting ducts, however, that lithium can accumulate in tissues and cause nephrotoxicity.¹³ Approximately 20% of lithium reabsorption occurs in the distal collecting duct, specifically in principal cells that primarily absorb sodium and water.¹³ Lithium in tubular fluid readily enters these cells via the epithelial sodium channel (ENaC) on the apical surface, as the form of ENaC in principal cells has 1.6 times greater affinity for lithium than it does for sodium (Figure).^37-39 Intracellular lithium accumulation can occur in certain patients primarily because lithium is a poor substrate for the sodium/potassium-ATPase pump on the basement membrane, and lithium efflux via the NHE1 transporter may be insufficient to compensate. Elevated intracellular lithium levels in principal cells impacts a number of molecular pathways with the net effect seen as decreased surface expression of water-absorbing aquaporin 2 (AQP2) protein channels, and insensitivity to aldosterone and vasopressin actions at AQP2 leading to AQP2 downregulation.¹³ The early clinical manifestation of this process is impaired water reabsorption, which the patient perceives as increased urinary frequency.³⁷

There are 2 important clinical sequelae of this process. The first is the risk of lithium refusal, as polyuria is among the top 3 AEs leading to discontinuation (diarrhea, 13%; tremor, 11%; polyuria/polydipsia, 9%).⁴⁰ If left untreated, the long-term impact may be renal microcyst formation, interstitial fibrosis, and tubular atrophy.¹⁴ Given the enormous effect that this process can have on patient adherence and long-term renal health, clinicians must inquire about urinary frequency at every visit and learn the tools to track severity and manage polyuria with amiloride, a potassium-sparing diuretic whose sole mechanism is ENaC antagonism.⁴¹

Concluding Thoughts

In general, clinicians are often aware of lithium’s efficacy profile, and research over the past 2 decades has provided guidance on ways to minimize lithium-related renal dysfunction through once-daily dosing at bedtime and the use of modest 12-hour serum levels based on values obtained on single nightly doses. That polyuria represents the initial manifestation of renal injury, that polyuria pathophysiology relates to lithium’s entry into collecting duct principal cells via ENaC and that amiloride is a specific treatment for this problem are often revelations to many clinicians.

When polyuria does occur, clinicians may not have been comfortable with tracking polyuria in a way other than asking the patient about severity.^10,11 Periodic assessment of intrinsic renal function using eGFR is the standard of care during lithium therapy, but this metric does not provide information on renal concentration problems. Moreover, although 24-hour urine collection is the gold standard for polyuria assessment,¹⁵ it has limitations in clinical practice, especially when repeated determinations might be necessary.

Part 2 of this series will discuss use of alternative methods (eg, 24-hour fluid intake record, early morning urine osmolality) to diagnose polyuria and quantify response to interventions.¹⁰ Armed with these tools and the understanding that use of an ENaC antagonist in the form of amiloride represents the most evidence-based treatment for lithium induced polyuria, clinicians may have more confidence in offering lithium and its therapeutic advantages to their patients.

Dr Meyer is a voluntary clinical professor of psychiatry at the University of California, San Diego.

References

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