Chronic Kidney Disease and Lithium: Update on a New Perspective

BIPOLAR UPDATE

Nephrotoxicity is a well-known adverse effect of lithium. Monitoring for nephrotoxicity and using lithium with great caution in patients with renal impairment are standards of care.¹ Over 4 years ago, I (DNO) wrote about new developments on this topic in Psychiatric Times, but the topic deserves to be revisited and updated.

The estimated glomerular filtration rate (eGFR) is an easily available routine measure for baseline and periodic monitoring of kidney function in patients on lithium.² Laboratories report eGFRs of less than 60 mL/min/1.73 m² as abnormal and indicating risk of chronic kidney disease (CKD). Stage 3 CKD, associated with an eGFR of 45 ± 14 mL/min/1.73 m², is defined as a level of impairment with significant potential for kidney failure and death over a 5-year period. One would usually want to avoid lithium or consider reducing or discontinuing it if the eGFR is 45-59 mL/min/1.73 m².

In a previous Psychiatric Times Bipolar Update, we discussed ways of dosing lithium and maintaining levels of lithium that minimize risk of kidney harm.³ These included using the immediate-release formulation (rather than long-acting versions), prescribing the full dose at night, keeping maintenance levels no higher than 0.6-0.8 mEq/L, and avoiding levels higher than 1.0 mEq/L at any time.

Questions have been raised about the longstanding adoption of a fixed threshold of less than 60 mL/min/1.73 m² for an abnormal eGFR for patients of all ages. GFR decreases with age, so not all reductions of eGFR during long-term lithium use are due to lithium. Moreover, these age-related eGFR reductions are not necessarily a reflection of clinically significant kidney disease. Although the aging kidney reliably develops some degree of nephrosclerosis and a reduction in measured whole-kidney GFR due to a decline in nephron count, the single-nephron GFR and glomerular size remain relatively constant in healthy aging.⁴ In contrast, albuminuria is not typically observed in healthy older adults and is independently associated with cardiovascular and noncardiovascular mortality.⁵ Without concomitant albuminuria, age-related eGFR decline has been shown to be associated with very modest to no increase in age-standardized mortality risk or end-stage renal disease.⁴

In light of the growing evidence that age-related eGFR decline is a distinct entity from CKD, a 2025 study sought to establish age- and sex-specific eGFR reference ranges for healthy adults.⁶ The authors included over 2.5 million European adults aged 18 to 107 years, of whom over 1.5 million were considered healthy, as they had no history of hypertension, diabetes, kidney disease, obesity, smoking, urine albumin to creatinine ratio of more than 30 mg/g, use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or several other exclusionary conditions. For the healthy 80-year-old patient, the 5th-percentile eGFR was 49 mL/min/1.73 m² in men and 46 mL/min/1.73 m² in women. On the other hand, the 5th-percentile eGFR for the healthy 20-year-old patient was 78 mL/min/1.73 m² in men and 81 mL/min/1.73 m² in women.

It has been proposed that the thresholds for CKD should be 75 mL/min/1.73 m² for patients younger than 40 years, 60 mL/min/1.73 m² for those aged 40 to 65 years, and 45 mL/min/1.73 m² for patients older than 65 years.⁷ Liu et al evaluated outcomes associated with CKD when defined by a fixed value (< 60 mL/min/1.73 m²) vs these age-adapted eGFR thresholds.⁸ Utilizing a population-based cohort of patients in the province of Alberta, Canada, they found, as expected, that CKD was diagnosed much more often in older adults using the standard threshold of less than 60 mL/min/1.73 m² compared with using a 45-mL/min/1.73 m² threshold. There were 2356 new cases per 100,000 person-years with the 60-mL/min/1.73 m² threshold vs 714 with the 45-mL/min/1.73 m² threshold. However, 75% of patients with eGFR values from 45 to 59 mL/min/1.73 m² were 65 years or older and had normal or only mild albuminuria. The 5-year risks of kidney failure and deaths among these older adults were similar to those of a control group of older adult patients without CKD with eGFRs from 60 to 89 mL/min/1.73 m². The absolute risk of kidney failure was 0.12% in both groups. The authors concluded that the current fixed eGFR criterion of 60 mL/min/1.73 m² seems to result in overdiagnosis of CKD in this aging population. These older adults likely underwent unnecessary evaluations and interventions when their problem was only age-related reduction in eGFR.

The implications for treating with lithium would seem to be that older adults (ie, older than 65 years) and some other patients with eGFRs of 45 to 59 mL/min/1.73 m² do not necessarily have CKD. Clinicians should evaluate these patients for proteinuria before making that diagnosis. Of course, close consultation with a kidney specialist would be advised regarding decisions about lithium use. However, it may be reasonable to start or continue to use lithium in more patients than was done prior to the emergence of this new perspective on the meaning of eGFRs.

Patients younger than 40 years, in contrast, were often underdiagnosed with CKD using the 60-mL/min/1.73 m² threshold. The study results found 14 vs 91 new cases of CKD per 100,000 person-years with the 60- and 75-mL/min/1.73 m² thresholds, respectively. The absolute rate of CKD was low. Still, it would seem prudent to remember the Alberta data and consult with a renal specialist if the eGFR is below 75 mL/min/1.73 m² in younger patients. Notably, however, results from studies of lithium maintenance in younger patients with bipolar disorder have not found declining eGFRs.⁹

Dr Osser is an associate professor of psychiatry at Harvard Medical School and lead psychiatrist of the US Department of Veterans Affairs’ National Bipolar Disorders Telehealth Program in Brockton, Massachusetts. Dr Padilla is a psychiatry resident at the Harvard South Shore Psychiatry Residency Training Program in Brockton, Massachusetts. The authors report no conflicts of interest concerning the subject matter of this article.

References

1. Taylor DM, Barnes TRE, Young AH. The Maudsley Prescribing Guidelines in Psychiatry. 15th ed. Wiley Blackwell; 2025:766-769.

2. Morriss R, Benjamin B. Lithium and eGFR: a new routinely available tool for the prevention of chronic kidney disease. Br J Psychiatry. 2008;193(2):93-95.

3. Osser DN. Tips for lithium dosing for optimal renal safety. Psychiatric Times. May 26, 2021. https://www.psychiatrictimes.com/view/tips-lithium-dosing-optimal-renal-safety

4. Hommos MS, Glassock RJ, Rule AD. Structural and functional changes in human kidneys with healthy aging. J Am Soc Nephrol. 2017;28(10):2838-2844.

5. Muzaale A, Khan A, Glassock RJ, et al. Kidney function assessment in the geriatric population. Curr Opin Nephrol Hypertens. 2024;33(2):267-271.

6. Astley ME, Chesnaye NC, Hallan S, et al. Age- and sex-specific reference values of estimated glomerular filtration rate for European adults. Kidney Int. 2025;107(6):1076-1087.

7. Delanaye P, Jager KJ, Bökenkamp A, et al. CKD: a call for an age-adapted definition. J Am Soc Nephrol. 2019;30(10):1785-1805.

8. Liu P, Quinn RR, Lam NN, et al. Accounting for age in the definition of chronic kidney disease. JAMA Intern Med. 2021;181(10):1359-1366.

9. Clos S, Rauchhaus P, Severn A, et al. Long-term effect of lithium maintenance therapy on estimated glomerular filtration rate in patients with affective disorders: a population-based cohort study. Lancet Psychiatry. 2015;2(12):1075-1083.