Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
Purine analog
Clofarabine
Clolar · Clofar
A second-generation purine analog whose systemic inflammatory storm can starve the kidney of perfusion.
ModeratePurine nucleoside analog · approved 2004
Pediatric relapsed/refractory acute lymphoblastic leukemiaAcute myeloid leukemia (off-label)
Signature kidney injury
Prerenal / Hemodynamic AKI
A systemic inflammatory response syndrome (SIRS) / capillary-leak syndrome with associated AKI was reported in roughly 4% of treated children in the registration program; hypotension was among the most common grade 3 or greater adverse events in the pivotal phase II trial. Precise renal incidence is not well quantified and most AKI data are case-level.
Source: Curran & Perry, Paediatr Drugs 2005; Jeha et al., J Clin Oncol 2006
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeverityModerate
ReversibilityPartially reversible
Evidence0 refs
Nephron map
Glomerulus
Vasculature / EndotheliumGlomerular & peritubular capillaries
Proximal Tubule
Distal Tubule / Collecting Duct
Prerenal / Hemodynamic AKI
Renal hypoperfusion from capillary leak and cytokine storm — IL-2 and CAR-T cytokine release syndrome.
Mechanism of kidney injury
The dominant lesion is hemodynamic. Drug-induced cytokine release (a SIRS / capillary-leak physiology, sometimes overlapping with a cytokine-release-like state during rapid cytoreduction) drives systemic vasodilation, third-spacing and intravascular volume depletion, producing prerenal AKI that can progress to ischemic acute tubular necrosis when hypotension is sustained. Concurrent tumor lysis at treatment initiation adds intratubular urate/phosphate load. Case-level and preclinical data also implicate direct proximal tubular injury and, rarely, a collapsing glomerulopathy-like picture attributable to ribonucleotide reductase inhibition.
Clinical presentation
Rising creatinine in the setting of tachycardia, hypotension, edema, hypoxemia and a SIRS picture, often within the first cycle; a concurrent rise in uric acid, phosphate and potassium signals tumor lysis. Proteinuria has been described in severe cases. Hepatotoxicity (transaminitis, hyperbilirubinemia) and skin rash frequently co-occur and help flag the systemic toxicity syndrome.
Onset
Early, typically within the first treatment cycle (days).
Reversibility
Partially reversible
Anticancer mechanism
Second-generation deoxyadenosine (purine nucleoside) analog phosphorylated intracellularly to clofarabine triphosphate, which inhibits ribonucleotide reductase (depleting the dNTP pool) and competitively inhibits DNA polymerase, terminating chain elongation. It also disrupts mitochondrial membrane integrity with release of cytochrome c and apoptosis-inducing factor, triggering apoptosis independent of cell division. Used for relapsed or refractory pediatric acute lymphoblastic leukemia and, off-label, refractory acute myeloid leukemia.
Management
Interrupt clofarabine immediately for signs of SIRS or capillary leak; provide aggressive fluid resuscitation and hemodynamic support (vasopressors as needed), and consider corticosteroids for systemic inflammatory features. Treat concurrent tumor lysis with hydration, rasburicase/allopurinol and electrolyte correction. Discontinue the drug for severe or progressive renal injury; renal replacement therapy is reserved for refractory metabolic derangements or volume overload. Most cases improve with drug withdrawal and supportive measures.
Risk factors
- High tumor burden / leukemic hyperleukocytosis
- Concurrent sepsis or hypotension
- Volume depletion
- Concomitant nephrotoxins
Prevention
- Vigorous IV hydration throughout the 5-day infusion course
- Tumor lysis prophylaxis (allopurinol or rasburicase) in at-risk patients
- Close monitoring for capillary leak / SIRS with early supportive care and consideration of corticosteroids for evolving SIRS
- Avoid concomitant nephrotoxins
Note · Renal injury is largely case-level; the SIRS/capillary-leak signal is the most consistently reported renal mechanism. The label carries a warning for capillary leak syndrome and SIRS.
Clinical depth
Renal dose adjustment
Limited renal pharmacokinetic data; the label advises starting at a reduced dose and monitoring closely when CrCl is 30-60 mL/min, and clofarabine is not recommended (avoid) when CrCl is below 30 mL/min. Renal clearance accounts for a substantial fraction of elimination, so impaired clearance raises systemic exposure.
Dialyzability & ESKD dosing
Not formally characterized; no established supplemental dosing for hemodialysis. Given its small size and renal elimination there is theoretical removal, but it is not used in dialysis-dependent patients and HD is employed only to manage AKI complications, not to dose the drug.
Differential diagnosis
Distinguish drug-induced SIRS/capillary-leak prerenal AKI from sepsis-associated AKI (blood cultures, procalcitonin), from tumor lysis nephropathy (urate/phosphate elevation, uric-acid:creatinine ratio), and from ischemic ATN on the basis of urine microscopy (muddy-brown granular casts favor established ATN) and the temporal link to hypotension during infusion.
Monitoring
- Vital signs and volume status frequently during each 5-day course (watch for hypotension/capillary leak)
- Serum creatinine and electrolytes daily during and after each cycle
- Uric acid, phosphate, potassium and calcium (tumor lysis) at initiation
- Liver enzymes and bilirubin (concurrent hepatotoxicity)
Key trials & series
- Jeha et al. phase II pediatric refractory/relapsed ALL trial (J Clin Oncol 2006) — basis of FDA approval
- Jeha et al. phase I dose-finding study (Blood 2003)
Clinical pearls
- Hypotension and capillary leak during the infusion are the key renal hazard — fluids and pressor support, not nephrotoxin avoidance alone, protect the kidney.
- Co-occurring transaminitis and rash should raise suspicion for the systemic toxicity syndrome that drives the AKI.
- Always layer tumor lysis prophylaxis on top, because rapid leukemic kill compounds the prerenal insult.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Glomerulus
Filtration barrier (podocytes + endothelium)
Injury signatures
Prerenal / Hemodynamic AKIAcute Tubular NecrosisGlomerular Injury / Proteinuria
Beyond the kidney
Class-level context for the major non-renal toxicities of purine analogs.
Gastrointestinal
Diarrhea, colitis, mucositis, perforation
- Mucositis and diarrhea
Hepatic / Liver
Transaminitis, hepatitis, VOD/SOS
- Transaminitis (methotrexate)
Hematologic
Cytopenias, thrombosis, TMA
- Myelosuppression
Pulmonary
Pneumonitis, ILD, effusions, hypertension
- Methotrexate / gemcitabine pneumonitis
Evidence
7 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkPhase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia.Jeha S et al. · J Clin Oncol 2006 · PMID 16622268Pivotal registration trial; hypotension among the most common grade >=3 adverse events, framing the hemodynamic/prerenal signal.PMIDClofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia.Jeha S et al. · Blood 2003 · PMID 14551141Phase I dose-finding study establishing the MTD and toxicity profile (hepatotoxicity, rash) of clofarabine.PMIDClofarabine: in pediatric patients with acute lymphoblastic leukemia.Curran MP et al. · Paediatr Drugs 2005 · PMID 16117562Reports capillary-leak/SIRS in treated children, the basis of the prerenal/perfusion signal.PMIDClofarabine-induced kidney toxicity.Jhaveri KD et al. · J Oncol Pharm Pract 2013 · PMID 24081220Case plus pharmacovigilance review of clofarabine AKI; proposes tubular/glomerular injury mechanism.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-stratified TLS prophylaxis framework relevant to the tumor-lysis component of clofarabine AKI.PMIDNew drug toxicities in the onco-nephrology world.Perazella MA et al. · Kidney Int 2015 · PMID 25671763Onco-nephrology review contextualizing newer agents including clofarabine.PMIDOnconephrology: The intersections between the kidney and cancer.Rosner MH et al. · CA Cancer J Clin 2020 · PMID 32853404Comprehensive onconephrology review covering drug-induced AKI and tumor lysis nephropathy.
Related agents
Other agents sharing the same signature kidney injury.