Lithium Nephrotoxicity

1. Nephrogenic Diabetes Insipidus (Ndi)

• Develops in up to 50% of long-term lithium users
• Polyuria (often 3-5 L/day), nocturia, polydipsia
• Risk of hypernatraemia if water access is restricted (surgery, dementia, sedation, illness)
• See separate guide for full management; amiloride is the drug of choice

2. Chronic Tubulointerstitial Nephropathy

• Develops over 10-20 years of lithium use
• Bland urine (minimal proteinuria, no haematuria) — closely mimics ADTKD
• Slowly progressive CKD
• 20-40% of long-term users develop eGFR <60
• Biopsy (rarely needed): tubular atrophy, interstitial fibrosis and characteristic microcysts in distal tubules and collecting ducts

3. Acute Lithium Toxicity

• Therapeutic range 0.4-1.0 mmol/L (often 0.6-0.8 for maintenance)
• Toxic: >1.5 mmol/L; severe >2.5 mmol/L
• Acute on chronic toxicity often precipitated by volume depletion, infection, NSAIDs, ACE/ARB, thiazides, dietary salt restriction
• Neurology: tremor, ataxia, confusion, myoclonus, seizures, coma
• GI: nausea, vomiting, diarrhoea
• Cardiac: T-wave changes, bradycardia, arrhythmia
• AKI from dehydration and direct tubular injury

4. Hypercalcaemia / Hyperparathyroidism

• Lithium shifts the calcium-sensing receptor set-point
• Develops in 10-30% of long-term users
• May persist after lithium discontinuation
• Can present with stones, fatigue, cognitive symptoms

5. Distal Rta And Hypokalaemia

• Less common but reported with chronic lithium use

6. NEPHROTIC SYNDROME (rare):

• Minimal change disease and FSGS reported with lithium
• Usually reverses with lithium discontinuation

BASELINE (before starting):

• eGFR, urea, electrolytes, calcium, magnesium
• Urine ACR
• Thyroid function
• BMI, BP
• ECG if >40 or cardiac risk
• Discussion of long-term renal and endocrine risks (consent)

ONGOING MONITORING (NICE CG185 / MHRA / RCPsych guidance):

• Lithium level every 3-6 months once stable (weekly until stable on a new dose)
• U&E, eGFR every 6 months at minimum (more often if CKD)
• Calcium every 6-12 months
• Thyroid function every 6-12 months
• Magnesium and parathyroid hormone annually or if calcium abnormal
• Urine ACR annually
• 24h urine volume if polyuria suspected
• BP at every review

ALERT TRIGGERS — discuss with nephrology:

• eGFR <60 sustained
• eGFR fall >5 ml/min/year
• ACR ≥3 mg/mmol
• Persistent polyuria with high serum sodium
• Hypercalcaemia
• Recurrent acute toxicity

DRUG INTERACTIONS — increase lithium toxicity:

• NSAIDs (including OTC ibuprofen)
• ACE inhibitors and ARBs
• Thiazide diuretics (less so loops)
• Metronidazole, tetracyclines
• SSRIs, tramadol (serotonin syndrome risk)
• Carbamazepine (neurotoxicity)
• Caution with low-sodium diet, dehydration, dialysis-related shifts

Assess

• Level (and timing of last dose)
• Symptoms — neurology, GI, cardiac
• Volume status
• eGFR
• Electrolytes — especially Na

Immediate Steps

• Stop lithium
• Stop NSAIDs, ACE/ARB, thiazides
• Discuss with poisons unit (TOXBASE / National Poisons Information Service)
• IV 0.9% sodium chloride to restore volume (typically 200-250 ml/h)
• Treat hypotension, seizures, arrhythmia
• Whole-bowel irrigation with polyethylene glycol if a recent overdose of slow-release tablets (within 1-2 hours)
• Activated charcoal NOT effective (lithium not adsorbed)

EXTRACORPOREAL REMOVAL (haemodialysis):

• Strongly consider when:
• Level >4 mmol/L (any patient)
• Level >2.5 mmol/L with severe symptoms, renal impairment, hypotension or heart failure
• Refractory severe symptoms regardless of level
• EXTRIP recommendations guide modality selection
• Intermittent haemodialysis is first-line (high clearance); may need repeat sessions for rebound from intracellular stores
• Continuous RRT can be used in haemodynamically unstable patients but is slower

Recovery

• Most acute toxicity resolves with supportive care and dialysis
• Persistent or new CKD common after severe toxicity
• Review lithium prescription with psychiatry — consider dose reduction, change to immediate-release, or alternative mood stabiliser

Principles

• Lithium is the most effective long-term mood stabiliser and the only drug shown to reduce suicide in bipolar disorder — stopping it carries real psychiatric risk
• Renal risk is real, especially after 15+ years of use
• The decision must be joint with psychiatry, the patient, and ideally a nephrologist

Consider Stopping / Switching

• eGFR <30 (some experts <45)
• Rapid fall in eGFR despite dose reduction
• Recurrent acute toxicity
• Significant proteinuria or biopsy-proven advanced lithium nephropathy
• Refractory NDI causing dangerous hypernatraemia
• Severe hyperparathyroidism requiring surgery

Alternative Mood Stabilisers

• Valproate (avoid in women of childbearing potential per MHRA Valproate Pregnancy Prevention Programme)
• Lamotrigine
• Atypical antipsychotics (quetiapine, olanzapine, aripiprazole)
• Combination therapies
• Switch ideally before significant kidney damage

If Continuing Lithium

• Lowest effective dose; lowest target level (often 0.4-0.6 mmol/L in older patients)
• Once-daily evening dose (gives a longer 'rest' for kidney exposure)
• Add amiloride 5-10 mg/day if NDI present
• Avoid co-prescribing NSAIDs, ACE/ARB (or use with caution and close monitoring)
• Sick-day rules: hold lithium during D&V, fever, restricted oral intake; resume after volume restored and a level checked

If Stopping Lithium

• Renal recovery is usually partial; CKD often progresses
• Hyperparathyroidism may persist
• NDI may persist for months-years
• Continue annual eGFR, ACR, BP, calcium

KEY MESSAGE: lithium nephrotoxicity is preventable in part — with monitoring, sick-day rules, drug-interaction awareness and timely joint reviews when warning signs appear.