Lithium Induced Nephropathy

Lithium induced nephropathy is kidney injury caused by long term lithium therapy. Lithium is the main long term treatment for bipolar disorder (affecting about 1% of people) and is also used for resistant depression.

It presents as:

• nephrogenic diabetes insipidus
• chronic tubulointerstitial nephritis with tubular microcysts
• less often, nephrotic syndrome, distal renal tubular acidosis and hypercalcaemia from hyperparathyroidism

Up to 40% of long term users develop nephrogenic diabetes insipidus, about 15 to 20% develop a reduction in eGFR below 60 mL/min/1.73 m², and 1 to 5% progress to kidney failure. Risk rises with years of exposure, with about 5 to 10 years of therapy before decline in many.

Acute lithium toxicity is a separate emergency causing neurological injury and acute kidney injury.

Pathophysiology. Lithium enters principal cells of the collecting duct through the epithelial sodium channel and accumulates, inhibiting glycogen synthase kinase 3 beta. This reduces aquaporin 2 expression and vasopressin response (nephrogenic diabetes insipidus). It also promotes cell proliferation, interstitial inflammation and fibrosis, with microcyst formation in distal tubules and collecting ducts. Lithium also stimulates parathyroid hormone release (raised calcium set point) and impairs distal acid secretion.

• Polyuria (more than 3 litres daily), polydipsia, nocturia; dilute urine (osmolality under 300 mOsm/kg) despite dehydration.
• Hypernatraemia when water intake is restricted, or in unwell and older patients.
• Chronic kidney disease: slowly progressive, bland urine, mild proteinuria (under 1 g daily); rarely nephrotic syndrome (minimal change disease or focal segmental glomerulosclerosis).
• Hypercalcaemia (raised parathyroid hormone in 10 to 20%), distal renal tubular acidosis, hypothyroidism (in 20 to 30%).
• Acute lithium toxicity: tremor, ataxia, slurred speech, confusion, myoclonus, seizures, vomiting, diarrhoea, arrhythmia.

Red flags

• Lithium level above 1.5 mmol/L, or any neurological features with a raised level.
• Acute kidney injury or dehydration in a lithium treated patient.
• Rapid fall in eGFR (more than 5 mL/min/1.73 m² each year) or eGFR under 45 mL/min/1.73 m².
• New medicines that raise lithium levels (NSAIDs, ACE inhibitors, angiotensin receptor blockers, thiazides, loop diuretics, metronidazole).
• Hypernatraemia above 150 mmol/L.

• Serum lithium (12 hours after the last dose), sodium, potassium, creatinine, eGFR, calcium, parathyroid hormone, phosphate, bicarbonate, thyroid function, glucose.
• Urine osmolality (random and after fluid restriction), 24-hour urine volume, desmopressin test (osmolality under 300 mOsm/kg after desmopressin 2 microg subcutaneously or 10 microg intranasally confirms nephrogenic diabetes insipidus; rises above 600 in central diabetes insipidus).
• Urine protein:creatinine ratio and albumin:creatinine ratio.
• Ultrasound or MRI of the kidneys: normal size, 1 to 2 mm cortical and medullary microcysts (diffuse, bilateral) that are highly characteristic.
• Kidney biopsy when proteinuria is above 1 g daily or the diagnosis is unclear: chronic tubulointerstitial nephritis with tubular atrophy, cortical and medullary microcysts, focal segmental glomerulosclerosis in a minority.

Differential diagnosis

• Central diabetes insipidus, primary polydipsia, osmotic diuresis (diabetes mellitus), hypercalcaemia, hypokalaemia, other causes of chronic tubulointerstitial disease and chronic kidney disease, polycystic kidney disease (macrocysts, enlarged kidneys), medullary sponge kidney.

Prevention and safe prescribing

• Check eGFR, sodium and calcium before starting lithium, at 3 months, then every 6 months (every 3 months if eGFR is under 60 or the dose changes). Check thyroid function every 6 to 12 months and lithium level every 3 months once stable.
• Maintain the level at 0.4 to 0.8 mmol/L (up to 1.0 mmol/L for acute mania), given as a single evening dose where possible, to reduce kidney exposure.
• Avoid NSAIDs and cyclo oxygenase 2 inhibitors, thiazides and loop diuretics, ACE inhibitors and angiotensin receptor blockers when possible, and metronidazole. If an ACE inhibitor or angiotensin receptor blocker is essential, reduce the lithium dose by 25 to 50% and recheck level in 5 to 7 days.
• Maintain hydration, and stop lithium temporarily during vomiting, diarrhoea, sepsis, surgery, radiocontrast or fasting.
• Review the risk and benefit of continuing lithium when eGFR is under 45, falling steadily (more than 3 mL/min/1.73 m² each year), or with nephrogenic diabetes insipidus that is poorly tolerated.
• Withdraw gradually over 4 to 8 weeks with psychiatry, because stopping abruptly raises relapse risk. Consider valproate, lamotrigine, quetiapine or olanzapine as substitutes.

Nephrogenic diabetes insipidus

• Fluid intake to match losses; avoid dehydration.
• Amiloride 10 mg daily (5 mg twice daily) increasing to 20 mg daily, which blocks lithium entry into the principal cell. Check potassium and creatinine at 1 and 2 weeks, and stop if potassium is above 5.5 mmol/L.
• Thiazide diuretic (hydrochlorothiazide 25 mg daily) only with halving of the lithium dose and weekly levels for 4 weeks (lithium levels rise by 25 to 40%). Add sodium restriction under 2 g daily, and low protein and low solute intake.
• Avoid indometacin and other NSAIDs for diabetes insipidus in lithium treated patients.

Acute lithium toxicity (urgent)

• Stop lithium. Check lithium, sodium, potassium, creatinine, calcium and ECG. Repeat the lithium level every 6 hours until falling (sustained release preparations rise late).
• Give intravenous 0.9% sodium chloride 1 to 2 litres over 2 to 4 hours, then 150 to 250 mL each hour, to restore volume and enhance clearance.
• Take caution with nephrogenic diabetes insipidus, which causes hypernatraemia: use 0.45% sodium chloride or 5% glucose when sodium exceeds 145 mmol/L.
• Extracorporeal treatment (haemodialysis, preferred) is indicated in any of these situations:
  • lithium above 4.0 mmol/L with impaired kidney function (eGFR under 45)
  • any neurological signs (confusion, seizures, reduced consciousness) with a level above 2.5 mmol/L
  • level above 5.0 mmol/L
  • time to reach a level under 1.0 mmol/L would exceed 36 hours
• Continue dialysis for at least 6 hours. Repeat when rebound occurs (check level at 6 to 12 hours after the end of dialysis).
• Activated charcoal does not bind lithium; use whole bowel irrigation for large sustained release overdoses.
• Observe for 24 hours after a level normalises.

Chronic kidney disease and complications

• Treat proteinuria and hypertension: ramipril 2.5 to 10 mg daily only if lithium cannot be changed (with lithium level monitoring); dapagliflozin 10 mg daily (eGFR at least 25) with care for volume depletion; blood pressure below 130/80 mmHg.
• Hypercalcaemia: refer for parathyroid assessment; cinacalcet 30 mg daily (maximum 180 mg) or parathyroidectomy; stop lithium if feasible.
• Distal acidosis: sodium bicarbonate 500 mg to 1 g two to three times daily to bicarbonate at least 22 mmol/L.
• Hypothyroidism: levothyroxine 1.6 microg/kg daily (lower in older adults), titrated to thyroid stimulating hormone 0.4 to 4 mIU/L.
• Kidney failure: dialysis at eGFR 5 to 10 with symptoms; transplantation with lithium replaced by another mood stabiliser.

Monitoring. Lithium level 5 to 7 days after any dose change or interacting drug; eGFR every 3 to 6 months; yearly urine albumin:creatinine ratio, calcium and thyroid function.

Referral and escalation. Nephrology when eGFR is under 45, a rapid decline occurs, proteinuria exceeds 0.5 g daily, or diabetes insipidus is severe; psychiatry before any change; urgent poisons unit and nephrology for toxicity.

Special groups

• Older adults: lower targets (0.4 to 0.6 mmol/L) and more frequent checks.
• Pregnancy: lithium level falls in pregnancy and rises after delivery; monitor monthly then weekly in the last month; decisions with psychiatry and obstetrics.
• Children and adolescents: monitor kidney function and thyroid function with the same checks and intervals used in adults.