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Written by:
Sejal Lakhani, DO
Internal Medicine Resident, Lehigh Valley Health Network, Allentown, PA
Rowan Zyada, MD
Nephrologist, Kidney and Urology Center, Alexandria, Egypt
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.
I- Introduction and Historical Review
Lithium is a light metal which can float in water. It is now used in batteries, a coolant inside nuclear power plants, and in fireworks.
Its use in medicine goes back to the 19th century when Alfred Baring Garrod (1819-1909) used lithium salts to treat gout and uric acid stones. Then John Cade reintroduced lithium to psychiatry for treatment of mania in 1949. He thought that manic depressive disorders were secondary to a toxic substance in the brain that is related to uric acid. While studying the toxic effect of uric acid on animals, he used lithium to make uric acid more soluble but the surprise he found that lithium urate had the opposite effect. He then chose to separate out the effects of lithium itself by using lithium carbonate, finding that it made guinea pigs very quiet.
Lithium is considered a mood stabilizer due to its effect on mood states in bipolar disorder. With the best overall evidence, it has been a mainstay in bipolar and other psychiatric disorder management for decades. In fact, it is the only medication that decreases the risk of suicide among patients with bipolar disorder.
In 2022, 393,262 patients in the United States were taking lithium making it the 212th most prescribed medication in the nation. However, once considered the gold standard therapeutic option for bipolar disorder, the long-term toxicity profile and other available mood stabilization options challenges this convention. Chronic lithium ingestion is associated with several forms of kidney disease. The most commonly reported kidney side effect is renal arginine vasopressin resistance (nephrogenic diabetes insipidus). Lithium is also associated with kidney function decline, which was first reported in a case series in the 1970s where patients were found to have chronic tubulointerstitial nephropathy on kidney biopsy, which was attributed to lithium. Additional kidney manifestations of lithium exposure include renal tubular acidosis and hypercalcemia.
In this blog post, we will delve into the intricacies of lithium-induced kidney injury, exploring its risk factors, clinical outcomes, and management strategies.
II- Renal Lithium Handling
Lithium is administered orally and is rapidly absorbed. Lithium has no clinically important protein binding properties as it redistributes to various tissues. Over 95% of the dose is excreted unchanged by the kidney. Lithium has a similar charge and size as sodium which results in similar filtration and reabsorption. Most of the filtered lithium is reabsorbed in the proximal tubule resulting in renal lithium clearance, which is approximately ⅕ of creatinine clearance.
Proximal tubule lithium reabsorption, similar to that of sodium, takes place through transcellular (⅓) and paracellular pathways (⅔). Lithium transporting proteins have not been identified but its uptake and transport is thought to be through the apical Na+/H+ exchanger and related basolateral NHE1. In the thick ascending limb of Henle, lithium is limited to paracellular transport, driven by the transcellular luminal positive electrical gradient established by the apical ROMK2 and NKCC2. In the distal tubule and collecting duct, transcellular lithium absorption occurs through ENaC and NHE1 channels.
Figure 2 from (Lithium in the Kidney: Friend or Foe?) Lithium reabsorption in different segments of the renal tubule and collecting duct.
Lithium has a narrow therapeutic index (0.6-1.2 meq/l). Medications alter lithium pharmacokinetics and as an elemental cation, it is expectedly altered by diuretics and sodium balance.
Concurrent medications/ pathologies present | Renal Clearance | Serum Lithium Levels |
Thiazide Diuretics | ↓ | ↑ |
Loop Diuretics | ↑ | ↓ |
Osmotic Diuretics | ↑ | ↓ |
↓ | ↑ | |
Volume Depletion | ↑ | |
Increased dietary sodium intake | ↓(promotes excretion) | |
Cirrhosis (sodium avid) | ↑(promote reabsorption) | |
CHF (sodium avid) | ↑(promote reabsorption) |
III. Lithium effects on the Kidney
Nephrogenic Diabetes insipidus (NDI)
Mechanism
Diabetes insipidus (DI) is a rare urinary concentrating disorder characterized by the passage of a large amount of diluted urine (hypotonic polyuria) and compensatory polydipsia. DI can occur due to reduced antidiuretic hormone (ADH) secretion from pituitary gland (central DI) or inadequate renal response to ADH (nephrogenic DI).
Lithium causes a nephrogenic DI (NDI). It does this by entering through epithelial Na channels (ENac) located on the apical membrane of the principal cells located in the collecting duct, resulting in nephrogenic desensitization to ADH leading to loss of urinary concentrating ability and polyuria. The main mechanisms by which this occurs are : 1) by inducing lysosomal degradation of AQP2 water channels and 2) inhibiting AQP2 gene transcription. It can also cause down-regulation of AQP2 expression.
Figure 3. Many sides of Lithium from @LittleBeans22 and @nefron1310
Water deprivation testing is crucial to distinguish between central DI, primary polydipsia and NDI. In patients with psychiatric illness, many psychiatric medications result in dry mouth increased thirst and polydipsia with resultant polyuria.
Incidence
The defect in urinary concentrating ability occurs as early as 2-4 months following initiation of lithium therapy while overt NDI develops over a longer period of time. The prevalence of NDI among lithium users ranges between 20- 87%. Overt NDI is seen in approximately 12% of those on lithium for 15 years or more. Polyuria and impaired renal concentrating ability is seen as frequently as 19% and 54%, respectively.
Risk factors
Risk factors for lithium induced NDI include long term duration of treatment, high serum lithium levels, twice daily dosing and use of slow release formulations.
Management
Initially, concentrating tubular defects are reversible with cessation of lithium. However, with continued treatment, this defect becomes overt and irreversible changes in renal medullary structure and function occur in up to 20% of unselected cases. If lithium can not be stopped, amiloride use is recommended. Amiloride is a potassium sparing diuretic which acts on the distal nephron resulting in inhibition of ENaC which reduces lithium uptake.
Other options aimed to address NDI include thiazide diuretics, which decrease water delivery to distal tubules and upregulate AQP2 water channels, and NSAIDs, which decreases prostaglandin production which is incriminated in principal cell death thereby reducing eGFR. The combination of desmopressin and NSAID therapies have also been suggested as they demonstrate improved urine osmolality among lithium users.
IV- Chronic Kidney disease (CKD)
A Fact or myth?
Chronic lithium ingestion is associated with progressive CKD secondary to chronic tubulointerstitial nephritis. While some renal biopsies from lithium treated patients showed high prevalence of interstitial fibrosis and tubular atrophy, further studies have reported contradictory results. Two meta-analyses (1, 2) failed to find conclusive evidence about lithium nephrotoxicity. Although worse renal function is present in patients treated with lithium, doubt remains regarding the magnitude and clinical significance. The effect of lithium may be confounded by multiple comorbidities affecting individuals with bipolar disorder, which includes metabolic syndrome and other lifestyle risk factors. However, the main drawback of these studies relate to the short duration of follow-up and short duration of lithium ingestion. Moreover, absence of pathognomonic pathological or biochemical changes makes lithium-associated CKD a diagnosis of exclusion. On the other hand, epidemiological studies using large databases found that prevalence of ESRD among chronic lithium users is 1.5%. Furthermore, there is almost an eightfold risk of ESRD among chronic lithium users when compared to the general population. Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) from the year 2000 suggests that between 0.2 to 0.7% of all new ESKD cases for that year were attributed to lithium induced nephropathy.
Figure 4 (from AJKD Atlas of Renal Pathology) : Lithium nephrotoxicity with microcytic dilatation at the corticomedullary junction with interstitial lymphocytic infiltrate associated with tubulointerstitial fibrosis and global glomerulosclerosis A: Jones silver stain, B: Masson trichrome stain
Risk factors
Identification of people who are at greater risk for lithium-induced nephropathy can help with early interventions to mitigate this risk. Higher risk patients include increased duration of therapy, old age, and episodes of over dosage/elevated lithium levels. Other factors include comorbidities like diabetes, hypertension, use of other nephrotoxic medications, concurrent use of angiotensin-converting enzyme (ACE) inhibitors, lithium-induced episodes of acute kidney injury, repeated episodes of nephrogenic diabetes insipidus, and the presence of concomitant CKD risk factors. A once daily dose regimen is associated with a lesser risk of toxicity compared to regimes with multiple dosing requirements per day. Persistent Lithium serum level > 0.6 mmol.L or single measure > 1.0 mmol/L can have a significant effect on eGFR.
Progression to ESRD
Lithium-induced nephropathy is slowly progressive. At least 20 years are needed to develop ESRD after lithium initiation. The rate of eGFR decline has been suggested to be an average of 2-3 mL/min per year of lithium exposure. GFR decline is higher among women, elderly population, those with a longer duration of lithium exposure, and higher cumulative dose.
Although discontinuation of lithium can improve eGFR, progressive kidney failure may ensure, especially in patients with severe renal impairment. Factors predictive of a poor prognosis include the degree of interstitial fibrosis on renal biopsy as well as the presence of heavy proteinuria. The degree of interstitial fibrosis on kidney biopsy may be directly related to the duration and cumulative dose of lithium.
A recent study investigating predictors of lithium associated kidney failure receiving kidney replacement therapy (KRT) using data from ANZDATA, found that patients with lithium-associated kidney injury were significantly older, more likely to be European, female, and have a higher socioeconomic status (SES).
Monitoring for GFR and drug level
Measurement of baseline serum creatinine and eGFR before initiation of lithium therapy and at subsequent 3-6 months intervals is recommended by the American Psychiatric Association. Lithium levels should also be monitored every 3 to 6 months or as otherwise clinically indicated.
The recommended serum lithium levels for the maintenance of bipolar disorder are between 0.5 to 0.8 mmol/L with higher levels of 0.8–1.2 mmol/L during the acute manic phase.
Use of lithium in CKD patients
If lithium is the cause of renal impairment, whether discontinuation will improve kidney function or prevent greater deterioration are questions without a conclusive answer. No evidence exists to tell when to stop lithium.
The decision should be individualized based on risk factors for CKD, duration of exposure, response to other antipsychotics, risk of bipolar disorder relapse, and suicide risk with the use of alternative therapeutic options. Lithium use in CKD patients should continue as long as treatment benefits outweigh the risks.
There is no clear evidence to support or dispute initiation of lithium in patients with already diagnosed CKD, however the decision should be individualized based on benefits of treatment and risks of progression to ESRD.
Figure (4) shows a suggested approach for management of patients with bipolar disorder undergoing lithium therapy.
Figure 5. a suggested approach for management of patients with bipolar disorder undergoing lithium therapy.
V- Others
Lithium use is also associated with development of distal RTA (type 1), minimal change disease, and focal segmental glomerulosclerosis (FSGS). However, underlying mechanisms and causal relation is not fully understood. Lithium use has also been associated with hyperparathyroidism either by inducing parathyroid hyperplasia or Increasing the threshold for the calcium-sensing mechanism within the parathyroid gland.
The nephrotoxic risks associated with lithium use should be carefully balanced with its important psychiatric benefits in patients with bipolar disorders. Despite uncertainty about the magnitude and clinical significance, it appears that long term use and high cumulative dose are the main risk factors for kidney injury. Elderly populations with many comorbidities are at higher risk so careful monitoring is recommended. Multidisciplinary team approach involving both nephrologists and psychiatrists is substantial for decision making.
AcademicCME (www.academiccme.com) is accrediting this educational activity for CE and CME for clinician learners. Please go to https://academiccme.com/kicr_blogposts/ to claim credit for participation.
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