Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
Ribonucleotide reductase inhibitor
Hydroxyurea
Hydrea · HU
An old ribonucleotide reductase inhibitor that, at high doses, can lyse blasts fast enough to flood the tubules.
MildRibonucleotide reductase inhibitor · approved 1967
Chronic myeloid leukemia / myeloproliferative neoplasmsHyperleukocytic acute leukemias (cytoreduction)Polycythemia vera and essential thrombocythemia
Signature kidney injury
Prerenal / Hemodynamic AKI
Acute tumor lysis syndrome from hydroxyurea is rare and reported at case level, almost exclusively with high-dose cytoreduction of leukemias carrying a high blast burden. Standard-dose hydroxyurea is not characteristically nephrotoxic.
Source: Seki et al., Ann Pharmacother 2003
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeverityMild
ReversibilityReversible
Evidence0 refs
Nephron map
Vasculature / EndotheliumGlomerular & peritubular capillaries
Distal Tubule / Collecting Duct
Tubular Lumen
Prerenal / Hemodynamic AKI
Renal hypoperfusion from capillary leak and cytokine storm — IL-2 and CAR-T cytokine release syndrome.
Mechanism of kidney injury
At high doses, rapid cytolysis of a proliferative blast population releases uric acid, phosphate and potassium; intratubular uric-acid and calcium-phosphate crystal/cast precipitation plus volume depletion produces obstructive and prerenal/ischemic AKI (tumor lysis nephropathy). Hydroxyurea itself is largely renally excreted but is not intrinsically tubulotoxic at usual doses.
Clinical presentation
Hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia and a rising creatinine within hours to a day of high-dose dosing, often accompanied by falling blast counts.
Onset
Very early (within 12-24 hours of high-dose treatment).
Reversibility
Reversible
Anticancer mechanism
Inhibits ribonucleotide reductase by quenching the tyrosyl free radical at its active site, depleting deoxyribonucleotides and arresting cells in S phase. Used to cytoreduce myeloproliferative neoplasms and the hyperleukocytosis of acute leukemias, and to raise fetal hemoglobin in sickle cell disease.
Management
Aggressive hydration, urate-lowering therapy (rasburicase for high-risk or established hyperuricemia) and electrolyte correction; hold high-dose hydroxyurea and provide supportive care, with hemodialysis for refractory hyperkalemia, hyperphosphatemia or oliguric AKI.
Risk factors
- High blast count / bulky proliferative disease
- High-dose hydroxyurea cytoreduction
- Volume depletion
- Baseline hyperuricemia or renal impairment
Prevention
- IV hydration to maintain high urine flow
- Allopurinol or rasburicase in at-risk patients
- Monitor uric acid, phosphate, potassium and creatinine when cytoreducing
Note · Standard-dose hydroxyurea is not typically nephrotoxic; the renal signal is treatment-related tumor lysis, chiefly at high doses. Because the drug is renally cleared, dose reduction is needed in CKD to avoid excess myelosuppression rather than nephrotoxicity.
Clinical depth
Renal dose adjustment
Hydroxyurea is predominantly renally excreted. The label and pharmacokinetic data support reducing the starting dose in renal impairment (commonly halving the dose when CrCl < 60 mL/min and using marked reductions or avoidance in ESKD) to prevent excessive myelosuppression; titrate to blood counts.
Dialyzability & ESKD dosing
Yes — hydroxyurea is a small (76 Da), water-soluble molecule that is readily removed by hemodialysis. In dialysis-dependent patients, dosing is commonly given after the HD session and reduced; counts must be followed closely.
Differential diagnosis
Tumor lysis nephropathy (urate/phosphate surge after rapid blast kill) versus leukostasis-related AKI in hyperleukocytosis versus prerenal azotemia from poor intake. Crystalluria (urate) on microscopy supports tumor lysis.
Monitoring
- CBC with differential frequently during cytoreduction
- Uric acid, phosphate, potassium, calcium and creatinine during high-dose/rapid cytoreduction
- Renal function periodically to guide dose in CKD
Key trials & series
- Seki et al. case series of high-dose hydroxyurea-precipitated acute tumor lysis (Ann Pharmacother 2003)
Clinical pearls
- Hydroxyurea nephrotoxicity is essentially tumor lysis at high cytoreductive doses, not chronic tubular injury.
- Because the drug is dialyzable and renally cleared, reduce the dose and dose post-HD in dialysis patients to avoid profound cytopenias.
- Hydration and urate-lowering therapy before aggressive cytoreduction are the key preventive steps.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Tubular Lumen
The urine flow path
Injury signatures
Prerenal / Hemodynamic AKIElectrolyte WastingCrystal / Obstructive Nephropathy
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkAcute tumor lysis syndrome secondary to hydroxyurea in acute myeloid leukemia.Seki JT et al. · Ann Pharmacother 2003 · PMID 12708945Cases of high-dose hydroxyurea precipitating acute tumor lysis syndrome with AKI.PMID[Tumor lysis syndrome].Downey AI et al. · Medicina (B Aires) 2019 · PMID 31829957Review noting hydroxyurea among non-classical triggers of tumor lysis syndrome.PMIDRecommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus.Cairo MS et al. · Br J Haematol 2010 · PMID 20331465Risk stratification guiding hydration and urate-lowering prophylaxis during cytoreduction.PMIDAn integrated clinical approach for the identification, prevention, and treatment of tumor lysis syndrome.Mughal TI et al. · Cancer Treat Rev 2009 · PMID 20031331Practical management of tumor-lysis AKI including the nephrologist's role.PMIDAnticancer Drug-Induced Acute Kidney Injury.Izzedine H et al. · Kidney Int Rep 2017 · PMID 29318217Onco-nephrology review of tumor-lysis and prerenal AKI mechanisms.PMIDOnconephrology: The intersections between the kidney and cancer.Rosner MH et al. · CA Cancer J Clin 2020 · PMID 32853404Reviews tumor lysis nephropathy and supportive renal management in cytoreductive therapy.
Related agents
Other agents sharing the same signature kidney injury.