How can lithium-induced renal function decline be prevented and managed in patients, particularly those with pre-existing renal conditions or taking other nephrotoxic medications?

Lithium and Renal Function Decline: Prevention and Management

Lithium causes progressive renal impairment in a substantial proportion of patients, but discontinuation when renal function begins to decline can prevent end-stage renal disease and often leads to improvement or stabilization of kidney function. 1, 2, 3

Baseline Assessment Before Initiating Lithium

Before starting lithium therapy, you must establish baseline kidney function and identify risk factors that increase nephrotoxicity risk 1:

• Measure baseline serum creatinine and calculate eGFR - serum creatinine alone is insufficient as it may appear normal despite reduced GFR, especially in elderly patients or those with reduced muscle mass 4
• Identify contraindications: significant renal disease, severe dehydration, sodium depletion, or concurrent diuretic use represent relative contraindications where lithium should only be used if life-threatening psychiatric indication exists 2
• Document pre-existing kidney disease or risk factors including hypertension, diabetes, cardiovascular disease, and age >65 years 1

Regular Monitoring During Lithium Treatment

Monitor kidney function, serum lithium levels, and electrolytes at least every 6 months, with more frequent monitoring during dose changes or acute illness 1:

• Measure serum creatinine and calculate eGFR every 6 months minimum 1, 2
• Check serum lithium levels to maintain therapeutic range (0.7-1.2 mmol/L) and avoid toxicity 5
• Monitor electrolytes including sodium, as depletion increases lithium retention and toxicity 2
• Perform urinalysis to detect early tubular dysfunction, as urine concentrating defects often precede GFR decline 6, 5
• Increase monitoring frequency to every 3-4 months if eGFR begins declining or drops below 60 mL/min/1.73m² 1

The evidence shows that approximately one-third of patients on lithium for 10-29 years develop chronic kidney disease (eGFR <60 mL/min/1.73m²), though severe impairment affects only about 5% 7. Importantly, research from the 1980s onward shows that end-stage renal disease is rare (<1.5%) when modern monitoring practices are followed 8, 7.

Avoiding Nephrotoxic Drug Combinations

Avoid NSAIDs in all patients taking lithium, as this combination significantly increases nephrotoxicity risk 9, 4, 1:

• NSAIDs should not be used concomitantly with lithium - this is a critical drug interaction that accelerates renal decline 9, 1
• Avoid or minimize other nephrotoxic agents including aminoglycosides, amphotericin, and high-dose cisplatin when possible 9, 4
• Exercise caution with RAAS inhibitors (ACE inhibitors, ARBs) - while not contraindicated, they require careful monitoring as they can affect renal hemodynamics 9, 4
• Avoid diuretics when possible, as they promote sodium depletion and increase lithium retention 2

The KDIGO guidelines emphasize that patients receiving three or more nephrotoxic drugs daily have substantially increased AKI risk, making drug stewardship essential 9.

Managing Intercurrent Illness

Temporarily discontinue lithium during serious intercurrent illness to prevent acute kidney injury and lithium toxicity 4, 1:

• Stop lithium during dehydrating illnesses (gastroenteritis, fever, excessive sweating) as dehydration causes lithium retention and toxicity 2
• Hold lithium before procedures requiring bowel preparation (avoid phosphate-containing preparations entirely in patients with eGFR <60 mL/min/1.73m²) 9, 4
• Suspend lithium before major surgery or IV radiocontrast administration 4
• Ensure adequate hydration during illness and after resuming lithium 1, 2

When to Reduce Dose or Discontinue Lithium

For progressive or sudden changes in renal function, even within the normal range, reevaluate treatment and consider dose reduction or discontinuation 2:

• eGFR 45-60 mL/min/1.73m²: Increase monitoring frequency to every 3 months, consider nephrology consultation, and evaluate risk-benefit of continuing lithium 1
• eGFR 30-45 mL/min/1.73m² (CKD Stage 3b): Strongly consider discontinuation or dose reduction with nephrology consultation, as this represents moderate-to-severe impairment 1
• eGFR <30 mL/min/1.73m² (CKD Stage 4): Discontinue lithium unless psychiatric indication is life-threatening and no alternatives exist 2

Research demonstrates that discontinuation of lithium leads to improvement in renal function or slower decline in the majority of patients, particularly those with eGFR >32 mL/min/1.73m² 3. Patients with CKD Stage 3 or worse who stopped lithium showed improvement or stabilization in the vast majority of cases 3.

Specific Monitoring for Tubular Dysfunction

Urine concentrating defects occur early and universally in lithium-treated patients, often before GFR decline 6, 5:

• Screen for polyuria and polydipsia at each visit, as these indicate nephrogenic diabetes insipidus 2, 6
• Perform urine concentration tests (urine osmolality after water deprivation or 24-hour urine volume) as the most sensitive marker of early lithium nephrotoxicity 2, 5
• Monitor for progressive decline in concentrating ability - inability to concentrate urine above 800 mOsm/kg water occurs in approximately 49% of long-term lithium patients 5

The longitudinal data show that tubular dysfunction (impaired urine concentration) and glomerular dysfunction (reduced eGFR) progress in parallel during lithium treatment, with mean decline of 140 mOsm/kg in concentrating ability over 4-5 years 6.

Common Pitfalls to Avoid

• Don't rely on serum creatinine alone - it underestimates renal impairment in elderly patients and those with low muscle mass; always calculate eGFR 4, 2
• Don't continue lithium indefinitely without monitoring - the risk of renal impairment increases with duration of treatment, with significant decline often occurring after 10+ years 8, 7, 5
• Don't ignore mild eGFR declines - progressive changes even within the normal range warrant reevaluation 2
• Don't prescribe NSAIDs to lithium patients - this combination is particularly nephrotoxic and should be avoided 9, 1
• Don't forget to hold lithium during acute illness - dehydration rapidly leads to lithium toxicity 4, 1, 2