Can valproic acid cause kidney disease?

Valproic Acid and Kidney Disease

Valproic acid can cause kidney tubular injury, particularly Fanconi syndrome, but does not typically cause chronic kidney disease or significant glomerular dysfunction in most patients. 1

Nature of Renal Injury

Valproic acid primarily causes proximal tubular injury rather than glomerular disease or progressive chronic kidney disease:

• Overt kidney tubular injury manifests with hypophosphatemia, normoglycemic glycosuria, tubular proteinuria, metabolic acidosis, hypouricemia, hypokalemia, and hypocalcemia after 7 months or more of treatment 1
• Histopathological findings show altered proximal tubular cells with giant and dysmorphic mitochondria on kidney biopsy 1
• Pauci-symptomatic injury is common, with isolated tubular proteinuria (particularly N-acetyl-β-glucosaminidase elevation) occurring in many patients on long-term therapy 1

Mechanism of Injury

The renal toxicity involves mitochondrial dysfunction and oxidative stress:

• Valproic acid causes mitochondrial depolarization, decreased ATP production, increased reactive oxygen species, and lipid peroxidation in renal tubular cells 2
• These mitochondrial abnormalities lead to proximal tubular dysfunction characteristic of Fanconi syndrome 2

Clinical Significance and Reversibility

The renal dysfunction is generally reversible and not clinically severe in most cases:

• Minor biochemical dysfunctions related to long-term therapy are reversible upon discontinuation 3
• Animal studies show no significant dose- or time-related permanent renal dysfunction, with minimal renal fibrosis that is not clinically important 3
• A slight reduction (27%) in unbound clearance occurs in patients with pre-existing renal failure (creatinine clearance <10 mL/minute), but no dosage adjustment is typically necessary 4

Monitoring Recommendations

Screen for tubular injury in patients on chronic valproic acid therapy:

• Monitor for biochemical markers of Fanconi syndrome (hypophosphatemia, glycosuria, metabolic acidosis, hypouricemia, hypokalemia) in patients treated for 7 months or longer 1
• Consider urinary tubular protein markers (N-acetyl-β-glucosaminidase) to detect subclinical injury 1
• Routine monitoring of serum creatinine and electrolytes is prudent, though severe progressive kidney disease is uncommon 4, 3

Important Caveats

• End-stage renal disease may be a risk factor for other valproic acid toxicities, such as pancreatitis 5
• The FDA label notes that protein binding is substantially reduced in renal failure patients, so monitoring total drug concentrations may be misleading as free concentrations may be elevated 4
• Paradoxically, valproic acid has shown protective effects in experimental models of adriamycin-induced nephropathy through its histone deacetylase inhibitor properties, though this is not clinically relevant for typical use 6