Clinical Neuroscience Lithium and kidney disease: Understand the risks Ziad A. Ali, MD, and Rif S. El-Mallakh, MD ithium is one of the most widely used reduced renal risk in patients with bipo- mood stabilizers and is considered a lar disorder.5 For example, Markowitz et Lfirst-line treatment for bipolar disorder al6 evaluated 24 patients with renal insuf- because of its proven antimanic and pro- ficiency after an average of 13.6 years of phylactic effects.1 This medication also can chronic lithium treatment. Despite stop- reduce the risk of suicide in patients with ping lithium, 8 patients out of the 19 bipolar disorder.2 However, it has a narrow available for follow-up (42%) developed Rif S. El-Mallakh, MD therapeutic index. While lithium has many ESRD.6 This study also found that serum Department Editor reversible adverse effects—such as tremors, creatinine levels >2.5 mg/dL are a predic- gastrointestinal disturbance, and thyroid tor of progression to ESRD.6 dysfunction—its perceived irreversible Discontinuing lithium is associated with nephrotoxic effects makes some clinicians high rates of mood recurrence (60% to 70%), hesitant to prescribe it.3,4 In this article, we especially for patients who had been stable describe the relationship between lithium on lithium for years.7,8 If lithium is tapered and nephrotoxicity, explain the apparent slowly, the risk of mood recurrence may contradiction in published research regard- drop to approximately 42% over the sub- ing this topic, and offer suggestions for how sequent 18 months, but this is nearly 3-fold to determine whether you should continue greater than the risk of mood recurrence in treatment with lithium for a patient who patients with good response to valproate develops renal changes. who are switched to another mood stabilizer (16.7%, c2 = 4.3, P = .048),9 which suggests that A lithium dilemma stopping lithium is particularly problematic. Many psychiatrists have faced the Considering the lifetime consequences of dilemma of whether to discontinue lith- bipolar illness, for most patients who have ium upon the appearance of glomerular been receiving lithium for a long time, the renal changes and risk exposing patients to recommendation is to continue lithium.10,11 relapse or suicide, or to continue prescrib- ing lithium and risk development of end stage renal disease (ESRD). Discontinuing Dr. Ali is a PGY-1 Psychiatry Resident, University of Kentucky College of Medicine, Bowling Green, Kentucky. Dr. El-Mallakh is Professor and lithium is not associated with the reversal Director, Mood Disorders Research Program, Department of Psychiatry Discuss this article at of renal changes and kidney recovery,5 and Behavioral Sciences, University of Louisville School of Medicine, www.facebook.com/ and exposes patients to psychiatric risks, Louisville, Kentucky. He is Section Editor for CURRENT PSYCHIATRY’S MDedgePsychiatry Clinical Neuroscience department. such as mood recurrence and increased Disclosures 6 risk of suicide. Switching from lithium Dr. Ali reports no financial relationships with any companies whose to another mood stabilizer is associated products are mentioned in this article, or with manufacturers of competing products. Dr. El-Mallakh is a speaker for Eisai, Indivior, with a host of adverse effects, including Intra-Cellular Therapies, Janssen, Lundbeck, Noven, Otsuka, diabetes mellitus and weight gain, and Sunovion, and Teva. Current Psychiatry 34 June 2021 mood stabilizer use is not associated with doi: 10.12788/cp.0130 Clinical Neuroscience Figure 1 The reasons for conflicting evidence Severe cyst formation Many studies indicate that there is either no statistically signifi- cant association or a very low association between lithium and developing ESRD,12-16 while others suggest that long-term lithium treatment increases the risk of chronic nephropathy to a clinically relevant degree (note that these arguments are not mutually exclusive).6,17-22 Clinical Point Much of this confusion has to MRI can detect do with not making a distinc- tion between renal tubular dys- renal microcysts in function, which occurs early and A severe case of cyst formation. Lithium-related microcysts are approximately 100% in approximately one-half of small (blue arrows). Larger cysts (red arrows) are not likely to be related to lithium, and are a common incidental and usually of patients receiving 23 patients treated with lithium, benign finding chronic lithium and glomerular dysfunction, Source: Dr. Luc Beuzit, Radiopaedia.org, rID: 38826 treatment and have which occurs late and is asso- ciated with reductions in glo- renal insufficiency merular filtration and ESRD.24 Adding to the confusion is that even without protective, and pro-reparative effects in lithium, the rate of renal disease in patients acute kidney injury.29 with mood disorders is 2- to 3-fold higher than that of the general population.25 Lithium Anatomical anomalies in lithium- treatment is associated with a rate that is related glomerular dysfunction higher still,25-27 but this effect is erroneously In a study conducted before improved exaggerated in studies that examined patients imaging technology was developed, treated with lithium without comparison to a Markowitz et al6 used renal biopsy to mood-disorder control group. evaluate lithium-related nephropathy in Renal tubular dysfunction presents 24 patients.6 Findings revealed chronic as diabetes insipidus with polyuria and tubulointerstitial nephritis in all patients, polydipsia, which is related to a reduced along with a wide range of abnormalities, ability to concentrate the urine.28 Reduced including tubular atrophy and interstitial glomerular filtration rate (GFR) as a con- fibrosis interspersed with microcyst forma- sequence of lithium treatment occurs in tion arising from distal tubules or collecting 15% of patients23 and represents approxi- ducts.6 Focal segmental glomerulosclerosis mately 0.22% of patients on dialysis.18 (FSGS) was found in 50% of patients. This Lithium-related reduction in GFR is a might have been a result of nephron loss slowly progressive process that typically and compensatory hypertrophy of surviv- requires >20 years of lithium use to result ing nephrons, which suggests that FSGS is in ESRD.18 While some decline in GFR may possibly a post-adaptive effect (rather than be seen within 1 year after starting lithium, a direct damaging effect) of lithium on the the average age of patients who develop glomerulus. The most noticeable finding ESRD is 65 years.6 Interestingly, short- was the appearance of microcysts in 62.5% term animal studies have suggested of patients.6 It is important to note that these Current Psychiatry that lithium may have antiproteinuric, biopsy techniques sampled a relatively Vol. 20, No. 6 35 Clinical Neuroscience Figure 2 Figure 3 Lithium-related microcysts, Lithium-related microcysts, example 1 example 2 Clinical Point Clinicians can use T2-weighted MRI A typical presentation of lithium-related to determine if microcysts in a 56-year-old woman with bipolar disorder receiving chronic lithium A typical presentation of lithium-related renal dysfunction is therapy with reduced glomerular filtration. microcysts in a 49-year-old woman with reduced Note the small size of the cysts (blue glomerular filtration (24 mL/min/1.73 m2) with related to lithium arrows), relatively random distribution, and microcysts (blue arrows) of random distribution, normal-sized kidneys and normal-sized kidneys Source: Dr. Luc Beuzit, Radiopaedia.org, rID: 38826 Source: Dr. Luc Beuzit, Radiopaedia.org, rID: 38826 small fraction of the kidney volume, and that insufficiency. One MRI study found renal microcysts might have been more prevalent. microcysts in all 16 patients.33 In another Recently, noninvasive imaging tech- MRI study of 4 patients, all were positive for niques have been used to detect micro- renal microcysts.34 The relationship between cysts in patients developing lithium-related MRI findings and renal function impair- nephropathy. While ultrasound and com- ment in patients receiving long-term lithium puted tomography (CT) can detect renal therapy is still not clear; however, 1 study microcysts, magnetic resonance imaging that examined 35 patients who received (MRI), specifically the half-Fourier acquisi- lithium reported that the number of cysts is tion single-shot turbo spin-echo T2-weighted generally related to the duration of lithium and gadolinium-enhanced (FISP three- therapy.35 Thus, microcysts seem to present dimensional MR angiographic) sequence, is long before the elevation in creatinine, and the best noninvasive technology to demon- nearly always present in patients with some strate the presence of renal microcysts of a glomerular dysfunction. diameter of 1 to 2 mm.30 Ultrasound is some- Cystic renal lesions have a wide variety times difficult to utilize because while classic of differential diagnoses, including simple cysts appear as anechoic, lithium-induced renal cysts; glomerulocystic kidney dis- microcysts may have the appearance of ease; medullary cystic kidney disease and small echogenic foci.31,32 When evaluated acquired cystic kidney disease; and mul- by CT, renal microcysts may appear as ticystic dysplastic kidney and autosomal hypodense lesions. dominant polycystic kidney disease.36 In Recent small studies have shown that patients who have a long history of lithium MRI can detect renal microcysts in approxi- use, lithium-related nephrotoxicity should mately 100% of patients who are receiving be added to the differential