Review of Lithium-Induced Renal Dysfunction – Pathophysiology | Diagnosis | Management

EPIDEMIOLOGY OF LITHIUM INDUCED RENAL DYSFUNCTION

Lithium is an evidence-based strategy in the treatment of bipolar disorder (BD). It shows efficacy in the treatment of acute mania and prophylaxis in BD in the prevention of manic episodes.

Lithium’s Mechanism of Action – A Synopsis and Visual Guide

Lithium Prescribing and Monitoring in Clinical Practice – A Practical Guide

Although the peak age of onset of bipolar disorder is between 15 and 24 years, it has been reported that 14% and 36% of patients are diagnosed during childhood (≤12 years) or adolescence (13 to 18 years), respectively. [Leverich et al 2007]

As such, a substantial number of middle-aged patients with bipolar disorder will be at risk of lithium-induced nephropathy due to receiving lithium for >20 years.

Lithium induced Nephropathy:

Chronic kidney disease (CKD) is defined as the presence of kidney damage or an estimated glomerular filtration rate (eGFR) less than 60 ml/min per 1.73 square meters, persisting for 3 months or more. The stages of chronic kidney disease are as follows:

Lithium induced nephropathy is a slowly progressive disease. The estimated eGFR declined by 0.71%/yr of age and 0.92%/year of treatment (30% more than that was associated with ageing alone), both by 19% more among women than men. [Tondo et al 2017]

Lithium is associated with an increased incidence (21-55%) of stage 3 CKD in those patients on long term lithium when compared to the general population.

Although only 4% of patients exhibit elevated serum creatinine levels after 6.5 years, this increases to 12% after 19 years of lithium therapy. [Muller-Oerlinhausen et al 2002]; [Belmaker 2004]

Epidemiological studies have shown that although renal insufficiency occurs in approximately 20% of patients, less than 1% of patients that have been administered lithium for >15 years develop end-stage renal disease [Bendz et, 2010].

While the relative risk of End-Stage Renal Disease (ESRD) compared to the general population is about eightfold, the estimated absolute incidence is low (0.2 to 0.7%).

Risk Factors: 

The association between lithium and nephropathy is however confounded by comorbidities.

Although eGFR is impaired and serum creatinine levels increase, it has been suggested that these findings are significantly confounded by several bipolar disorder related lifestyle risk factors such as the increased risk for metabolic syndrome. [McCann et al 2008]; [McKnight et al 2012]

Clos et al. found that after adjustment for comorbidities, other medication use, and episodes of lithium toxicity in a longitudinal cohort study they found no increase in the risk of renal dysfunction for those who have a baseline eGFR higher than 60 ml/min/1.73m²    [Clos et al, 2015]

Thus, it is unclear how direct the risk is for developing lithium-induced nephropathy. Risk factors associated are as follows:

• Age: Until the fourth decade of life glomerular function remains well maintained, but thereafter it declines by about 8 ml/min/1.73 m2 body surface area per decade [Weinstein & Anderson,2010].
• Female sex
• Longer duration of use
• Total cumulative lithium dose
• Lithium levels: Increasing risk with greater lithium trough levels, such that odds of renal failure are more than twofold greater among individuals with lithium levels of 0.8 mEq/l or greater. [Castro et al, 2016]
• Twice daily dosing
• Immediate release preparation (IR): Prolonged-release (PR) formulations compared to IR formulations are found to produce less impairment of the kidney to concentrate urine. This is likely due to fewer concentration peaks and more stable concentrations of lithium. [Girardi, et al, 2016]
• Lower initial GFR value
• The use of other nephrotoxic medications such as angiotensin-converting enzyme inhibitors (ACE-I), angiotensin II receptor blockers (ARB), non-steroidal anti-inflammatory agents (NSAIDs) and thiazide diuretics,
• NDI: Once NDI is established it may also persist despite the cessation of lithium therapy suggesting that the prolonged use of lithium can lead to irreversible changes in renal structure and function
• Increased number of lithium intoxication episodes: Even one serum level of lithium > 1.0 mmol/L can cause a significant effect on eGFR up to 3 months after exposure, and lithium-induced episodes of acute kidney injury have been associated with longer-term risk for the development of CKD. [Davis et al, 2018]
• Preexisting somatic conditions (diabetes, hypertension, obesity, cardiovascular disease, and hyperparathyroidism). [Freeman and Freeman 2006]

Diabetes Insipidus 

PATHOPHYSIOLOGY OF LITHIUM INDUCED RENAL DYSFUNCTION

Lithium is a monovalent cation filtered through the glomeruli with ≤80% reabsorbed in the proximal renal tubule.

However, a tiny fraction is reabsorbed through the epithelial sodium channel (ENaC), which then accumulates in the distal parts of the nephron, where it inhibits glycogen synthase kinase (GSK-3β). [Rao et al. 2005]

GSK-3β is primarily involved in glycogen metabolism but is also associated with regulating water and sodium transport in the kidney. [Gould and Manji 2005]

GSK-3β has been hypothesised to play a central role in the molecular effects of lithium-induced tubular dysfunction. During lithium treatment:

• Regulation of ENaC expression is downregulated, thus increasing the fractional excretion of sodium (natriuresis).
• The downregulation of aquaporin 2 (AQP2) water channels along the collecting duct causes water diuresis.

Overall, this lithium-induced downregulation causes a partial insensitivity to aldosterone (regulates ENaC) and vasopressin (regulates AQP2), which form the body’s homeostatic maintenance of acid-base levels.

Therefore, it is surmised that prolonged lithium treatment is associated with distal tubular acidosis, which then manifests into interstitial fibrosis and CKD.

DIAGNOSIS OF LITHIUM INDUCED RENAL DYSFUNCTION

Early identification of nephrotoxicity requires regular renal function monitoring, with the NICE guidelines recommending testing every 6 months and the APA recommending every 2 to 3 months during the first 6 months followed by 6-month intervals [APA 2002] ; [NICE 2014].

Measuring only serum urea and creatinine is no longer preferred with eGFR calculations now standard practice.

• An eGFR test is prone to a false positive, especially in those who are obese and as such consecutive eGFR tests should be performed to detect progressive deterioration.
• Three eGFR tests should be performed over a period of ≥90 days to extrapolate progressive deterioration in renal function.
• Overt proteinuria should be further quantified with a urine protein to creatinine ratio.

Not all patients taking lithium experience glomerular adverse effects, with only 40% of patients reporting mild symptoms of polyuria, nocturia, and polydipsia. [Stone 1999]

However, lithium-induced nephropathy is typically asymptomatic with no proteinuria present and measures such as a patient’s urinary sediment levels are generally reported as normal.

The evidence for lithium-induced proteinuria as a marker for nephropathy is unclear despite its utility in predicting CKD.

Guideline recommendations on the parameters that should be monitored, as well as the frequency of monitoring, are heterogeneous with a substantial variety of factors that need to be considered before a decision on whether to cease lithium therapy [Davis et al. 2018]:

• Medical history review, including cardiovascular, urological, and medication history (notably for BP management)
• BMI and lipid profiles (HDL, triglyceride levels, and fasting glucose)
• Blood counts, calcium levels, and measurement of liver function, thyroid and parathyroid function
• Serum lithium levels according to guidelines; maintenance treatment in BD (approximately 0.5 to 0.8 mmol/L), with higher levels of 0.8–1.2 mmol/L generally only recommended during the acute manic phase of the illness. [Read more on practical prescribing of lithium]
• A paired serum and urine osmolality measurement via a 24-h urine collection (which will also provide urine volume levels) is required if symptoms of NDI are present.
• The risk of relapse of bipolar disorder based on a patient’s psychiatric history

However, discontinuation only minimally reverses tubular dysfunction, with research showing that kidney function may remain abnormal due to irreversible renal structure and function changes. [Presne et al. 2003]; [Moss et al. 2014]

Furthermore, evidence-based literature analysis has also suggested improvements are only feasible during the first 6 years of lithium exposure. [Grandjean and Aubry 2009]

TREATMENT OF LITHIUM INDUCED RENAL DYSFUNCTION

Lithium is an established and gold standard psychotropic drug for bipolar disorder, and a careful risk-benefit analysis should be carried out before lithium cessation is considered.

Prevention:

• A once-daily dose of lithium, independent of whether the preparation is sustained release or immediate release, may confer a lower risk of renal insufficiency than regimes with multiple dosing requirements per day.
• However, if feasible, it is worth considering reducing the lithium dose to a serum level that is at the lowest end of the therapeutic range [Grandjean and Aubry 2009]

Management of Renal Dysfunction with Lithium

Lithium induced nephropathy may continue to progress despite cessation of lithium and may even do so at a relatively innocuous creatinine clearance of <40 ml/min or creatinine level of < 220 mmol/L (a time where patients could still be asymptomatic from their CKD). Therefore guidelines have proposed a lower creatinine clearance level to involve specialist nephrology input. [Davis et al. 2018]

Indications for a Nephrology Referral: [Davis et al. 2018], [Gupta et al., 2013

• eGFR < 30 ml/min/1.73m2
• Progressive decline in the eGFR (especially if decreased by > 4 ml/min/1.73m2 / yr)
• Rapidly declining eGFR (>5 ml/min/1.73 m2 over 1 year, or >10 ml/min/1.73 m2 over 5 years)
• Potential complications of CKD such as anaemia
• Creatinine level of 140 mmol/L
• If the patient has stage 4 or 5 chronic kidney disease
• Proteinuria (ACR ≥30 mg/mmol, roughly equivalent to PCR ≥50 mg/mmol, or urinary protein excretion ≥0.5 g/24 h) together with haematuria
• Heavy proteinuria (ACR ≥70 mg/mmol, roughly equivalent to PCR ≥100 mg/mmol, or urinary protein excretion ≥1 g/24 h) unless known to be due to diabetes and already appropriately treated

Lithium discontinuation

Lithium discontinuation and replacement with an alternative should be considered; however, this needs to be weighed up against the significant increase in relapse and suicidal risk.

A study looked to establish whether lithium or anticonvulsant should be used for maintenance treatment for bipolar affective disorder (BPAD) if the risks of suicide and relapse were traded off against the risk of end-stage renal disease (ESKD). The final endpoint was 30 years of treatment with five outcomes: death from suicide, alive with stable or unstable BPAD, alive with or without ESRD.

The authors concluded :

Lithium initiation and continuation, even in the presence of long-term adverse renal effects should be recommended in most cases.

Discontinuation of lithium leads to improvement in renal function or at least less rapid deterioration in most patients.[Hoekstra et al., 2022]

A process of shared informed decision making is essential, incorporating the person’s viewpoint on the available choices and their consequences. This is a decision best made gradually over time, in consultation with their treating psychiatrist, nephrologist, primary care physician and significant others if appropriate. If lithium is ceased, this should be done very gradually and with close monitoring, together with understanding of early warning signs and engagement of caregivers if appropriate. [Davis et al. 2018]

Management of Diabetes Insipidus (NDI)

• Exclude other causes
• If significant functional impact: order 24 hr urine volume and osmolality
• Reduce dose or once-daily dosing
• Liaise with nephrology
• Risk-benefit analysis
• If lithium is continued Thiazide, Amiloride or Indomethacin are options

Thiazide

• Decreases extracellular fluid volume and encourages proximal tubular absorption; however, thiazides can cause a compensatory increase in sodium chloride reabsorption and an accumulation in lithium when the drugs are co-administered.

Amiloride:

• Potassium-sparing diuretic which blocks the epithelial sodium channel ENaC thus preventing lithium uptake and partially reversing lithium-induced nephropathy making it the current standard of care. [Schoot et al. 2020]
• Amiloride is less effective in severe cases, and in these cases, indomethacin is preferred.

Indometacin:

• Inhibits prostaglandins.
• However, vigilance is needed here because of the possibility of lithium toxicity in the short term and the direct nephrotoxic effect of indomethacin in the long term.

SUMMARY

There is substantial epidemiological, biological, and clinical data that show long-term lithium therapy increases the risk for CKD.

For some patients, lithium therapy is of paramount importance and therefore discontinuation may not be feasible due to the risk of relapse.

At present, there is a strong requirement for a collaborative decision-making process to guide the management of patients with lithium-induced nephropathy.