Should hydroxyurea (hydroxycarbamide) be increased in a sickle cell patient with hyperbilirubinemia and impaired renal function?

Hydroxyurea Dosing in Sickle Cell Disease with Elevated Bilirubin and Creatinine

Hydroxyurea dose should be reduced, not increased, in sickle cell patients with elevated bilirubin and creatinine due to increased drug exposure and risk of toxicity. 1

Impact of Renal Impairment on Hydroxyurea Pharmacokinetics

• Patients with creatinine clearance <60 mL/min and those with end-stage renal disease (ESRD) have approximately 64% higher exposure to hydroxyurea compared to patients with normal renal function 1
• Systemic exposure to hydroxyurea increases and urinary recovery decreases as the degree of renal insufficiency worsens 2
• Reduced renal function affects hydroxyurea elimination, leading to drug accumulation and potential toxicity 3

Recommended Dosing Adjustments

• For sickle cell disease patients with creatinine clearance <60 mL/min, the FDA recommends reducing the hydroxyurea dose and closely monitoring hematologic parameters 1
• An initial dosing regimen of 7.5 mg/kg/day (half the standard dose) has been proposed for SCD patients with creatinine clearance <60 mL/min 2
• Monitoring of estimated glomerular filtration rate (eGFR) and body weight is recommended, as these factors account for 47% of hydroxyurea pharmacokinetic variability 3

Renal Considerations in Sickle Cell Disease

• Kidney disease is a major contributor to morbidity and mortality in sickle cell disease 4
• Albuminuria is an early manifestation of sickle cell nephropathy and is highly prevalent in SCD patients 4, 5
• Older individuals with SCD have lower than expected eGFR, particularly those with HbSS genotype 4

Potential Benefits of Hydroxyurea in Renal Function

• Hydroxyurea use is associated with a lower likelihood of albuminuria in sickle cell patients (odds ratio 0.28,95% CI: 0.11-0.75) 5
• In some cases, combination therapy with hydroxyurea and enalapril has been shown to normalize urine protein/creatinine ratios in children with sickle nephropathy 6
• The American Society of Hematology suggests combination therapy with hydroxyurea and erythropoiesis-stimulating agents for SCD patients with chronic kidney disease and worsening anemia 7

Monitoring Recommendations

• Close monitoring of hematologic parameters is essential when administering hydroxyurea to patients with renal impairment 1
• Bone marrow suppression (decreased counts in one or more cell lines) is common with hydroxyurea therapy and requires temporary discontinuation if severe 7
• For patients receiving combination therapy with erythropoiesis-stimulating agents, hemoglobin levels should not exceed 10 g/dL to reduce the risk of vaso-occlusive complications 7
• Monitor for signs of hepatic dysfunction, as elevated bilirubin may indicate ongoing hemolysis or liver involvement 4

Clinical Decision Algorithm

1. Assess current renal function (calculate creatinine clearance)
2. If creatinine clearance <60 mL/min:
   • Reduce hydroxyurea dose to 7.5 mg/kg/day 2
   • Monitor complete blood count weekly until stable dose established 1
3. If patient has both elevated bilirubin and creatinine:
   • Consider causes of elevated bilirubin (hemolysis vs. hepatic dysfunction)
   • Maintain reduced hydroxyurea dose until renal function improves 1
4. For patients with chronic kidney disease and worsening anemia:
   • Consider adding erythropoiesis-stimulating agents rather than increasing hydroxyurea 7

In conclusion, the evidence strongly indicates that hydroxyurea dose should be reduced, not increased, in sickle cell patients with elevated bilirubin and creatinine to prevent drug accumulation and toxicity while maintaining therapeutic benefits.