What are the effects of hydroxyurea on the kidneys, particularly in patients with pre-existing renal impairment or those with cancer/sickle cell disease?

Hydroxyurea's Effects on the Kidneys

Hydroxyurea requires dose reduction in patients with renal impairment (CrCl <60 mL/min) due to 64% higher drug exposure, but paradoxically may improve early sickle nephropathy by reducing glomerular hyperfiltration in patients with sickle cell disease. 1, 2

Pharmacokinetic Impact of Renal Impairment

Hydroxyurea exposure increases substantially when kidney function declines:

• Patients with creatinine clearance <60 mL/min or end-stage renal disease (ESRD) have 64% higher hydroxyurea exposure (AUC) compared to those with normal renal function 1
• Approximately 40% of an oral hydroxyurea dose is excreted unchanged in urine, making renal function a critical determinant of drug clearance 1
• The FDA mandates dose reduction when administering hydroxyurea to patients with CrCl <60 mL/min or ESRD on hemodialysis 1
• An initial dosing regimen of 7.5 mg/kg/day (rather than the standard 15-20 mg/kg/day) is recommended for sickle cell disease patients with CrCl <60 mL/min 3

Beneficial Effects on Sickle Nephropathy

Hydroxyurea therapy appears to protect against early kidney damage in sickle cell disease:

• In children with sickle cell anemia treated with hydroxyurea at maximum tolerated dose for 3 years, glomerular filtration rate decreased from 167 ± 46 mL/min/1.73 m² to 145 ± 27 mL/min/1.73 m², representing normalization of pathologic hyperfiltration 2
• This reduction in hyperfiltration was significantly associated with increased fetal hemoglobin and decreased lactate dehydrogenase levels, suggesting disease modification 2
• Among children with baseline albuminuria, median urine albumin-to-creatinine ratio decreased from 96 mg/g before hydroxyurea to 39 mg/g at 1 year and 25 mg/g at 2 years 4
• Albuminuria normalized in 61% of patients after 2 years of hydroxyurea therapy 4

The mechanism appears to be reduction of hemolysis and sickling rather than direct nephrotoxicity, as glomerular hyperfiltration is an early pathologic feature of sickle nephropathy that hydroxyurea helps reverse. 2

Management in Chronic Kidney Disease

For sickle cell disease patients with chronic kidney disease and worsening anemia, combination therapy with erythropoiesis-stimulating agents (ESAs) allows continued or more aggressive hydroxyurea dosing:

• The American Society of Hematology suggests combining hydroxyurea with ESAs in this population to counteract treatment-related anemia while maintaining disease-modifying therapy 5, 6
• Hemoglobin must be maintained ≤10 g/dL (hematocrit ≤30%) when using combination therapy to prevent hyperviscosity, vaso-occlusive complications, stroke, and venous thromboembolism 5, 7, 6
• ESAs allow more aggressive hydroxyurea dosing by counteracting anemia, potentially slowing progression of end-organ damage including kidney disease 5, 6
• Only 1 of 56 patients (1.8%) experienced worsening sickle cell symptoms with combination therapy, suggesting a favorable safety profile 5

Monitoring Considerations

Close hematologic monitoring is essential, particularly in renal impairment:

• Bone marrow suppression is the most common dose-limiting toxicity but typically resolves within 2 weeks of temporary drug discontinuation 5, 7
• Estimated GFR and body weight together account for 47% of hydroxyurea pharmacokinetic variability and should guide dosing 8
• Elderly patients are at higher risk for adverse reactions due to age-related decline in renal function and require careful dose selection 1

Important Caveats

• Hydroxyurea is not directly nephrotoxic—the dose reduction requirement in renal impairment is due to decreased drug clearance and risk of systemic toxicity, not kidney-specific toxicity 1, 3
• The beneficial effects on albuminuria and hyperfiltration are specific to sickle cell disease and reflect disease modification rather than a direct renal protective effect applicable to other conditions 2, 4
• NT-pro-BNP measurements for risk stratification in sickle cell disease may be misleading in patients with renal insufficiency 5