Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
Enzyme (asparaginase)
Pegaspargase
Oncaspar · PEGA
An enzyme whose kidney injury is never direct — find the mediating thrombosis, pancreatitis, or tumor lysis.
MildEnzyme (asparaginase) · approved 1994
Acute lymphoblastic leukemia (first-line multi-agent regimens; and in patients with hypersensitivity to native asparaginase)
Signature kidney injury
Prerenal / Hemodynamic AKI
Direct nephrotoxicity is not recognized; AKI is indirect and uncommon. For context, symptomatic thrombosis occurs in ~1.5-5% of children and is higher (~5-10%+) in adults/adolescents-and-young-adults, and clinical pancreatitis in ~5-10%. A drug-specific AKI incidence is not quantified (it is a downstream complication, not a tracked endpoint).
Source: Place et al., Lancet Oncol 2015
Mechanism of kidney injury
Indirect, predominantly pre-renal/hemodynamic and vascular: (1) asparaginase-associated thrombosis from depletion of liver-synthesized antithrombin, protein C/S, fibrinogen and plasminogen creates a prothrombotic state (including renal-vein/venous thrombosis); (2) pancreatitis with third-spacing and hypovolemia causes prerenal AKI/ATN; (3) hypertriglyceridemia/hyperviscosity and induction tumor lysis add further mechanisms. There is no characteristic direct tubular lesion.
Clinical presentation
Falling antithrombin and fibrinogen during therapy; thrombosis usually during induction/first weeks (often CNS sinus or DVT, occasionally renal vein with flank pain, hematuria and a rising creatinine). Pancreatitis presents with abdominal pain and lipase/amylase >3x ULN days to weeks after a dose.
Onset
Toxicities cluster during induction/first doses; AKI is usually reversible with treatment of the underlying thrombosis or pancreatitis.
Reversibility
Reversible
Anticancer mechanism
PEGylated E. coli L-asparaginase that hydrolyzes circulating L-asparagine (and some glutamine). Acute lymphoblastic leukemia (ALL) blasts lack asparagine synthetase and depend on extracellular asparagine, so depletion starves them, halting protein synthesis and inducing apoptosis. PEGylation extends the half-life (~5-7 days) and lowers immunogenicity, allowing every-2-week dosing.
Management
Treat the mediating event: therapeutic anticoagulation (usually LMWH) for thrombosis — note that antithrombin depletion blunts heparin efficacy, so antithrombin repletion may be needed — and hold asparaginase during acute thrombosis. Permanently discontinue for severe/necrotizing or recurrent pancreatitis. Resuscitate volume for prerenal AKI.
Risk factors
- Adolescent/young-adult or adult age and high-risk ALL
- Higher cumulative dose and central venous catheters
- Concurrent steroids, thrombophilia, obesity, hypertriglyceridemia
Prevention
- Hydration and central-line care; tumor-lysis prophylaxis at induction
- Consider antithrombin replacement and/or LMWH thromboprophylaxis in higher-risk patients
- Monitor antithrombin, fibrinogen, amylase/lipase and triglycerides
Note · Established (1994) agent; renal events are downstream of thrombosis/pancreatitis/tumor lysis and not separately quantified.
Clinical depth
Renal dose adjustment
The enzyme is cleared by reticuloendothelial/proteolytic mechanisms, not renally excreted, so no renal dose adjustment is required. Hold or adjust for pancreatitis, serious thrombosis/hemorrhage, or severe hypersensitivity — not for creatinine.
Dialyzability & ESKD dosing
Not meaningfully dialyzable (a large PEGylated protein); hemodialysis is not used for removal.
Differential diagnosis
Tumor-lysis urate/phosphate nephropathy, sepsis/ATN, nephrotoxic co-medications (vancomycin, contrast, methotrexate), pancreatitis-related hypovolemia, renal-vein/venous thrombosis, leukemic infiltration and hyperviscosity.
Monitoring
- Antithrombin activity and fibrinogen (and serum asparaginase activity where available)
- Amylase/lipase, glucose and triglycerides
- LFTs/bilirubin and coagulation (PT/PTT)
- Renal function and uric acid at induction
Key trials & series
- DFCI 05-001 (Place, Lancet Oncol 2015) — pivotal phase 3 establishing IV pegaspargase front-line
- CCG-1962 (Kurre, J Pediatr Hematol Oncol 2002) — companion randomized registrational study
Clinical pearls
- AKI is almost never direct drug toxicity — find the mediating event (thrombosis, pancreatitis, or induction tumor lysis).
- Antithrombin is the linchpin: depleted antithrombin both causes the prothrombotic state and blunts heparin — check and repkete it when anticoagulating.
- It is an enzyme — not renally cleared and not dialyzable; dose tracks toxicity, not creatinine.
- Hold rather than dose-reduce for serious events; discontinue for severe pancreatitis.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Prerenal / Hemodynamic AKIAcute Tubular Necrosis
Evidence
7 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkIntravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial.Place AE et al. · Lancet Oncol 2015 · PMID 26549586Pivotal phase 3 establishing IV pegaspargase as front-line asparaginase.PMIDPharmacokinetic/pharmacodynamic relationships of asparaginase formulations: the past, the present and recommendations for the future.Avramis VI et al. · Clin Pharmacokinet 2005 · PMID 15828851Mechanism/PK-PD of asparagine depletion; PEGylation extends half-life.PMIDThe coagulopathy and thrombotic risk associated with L-asparaginase treatment in adults with acute lymphoblastic leukaemia.Truelove E et al. · Leukemia 2012 · PMID 23099335Antithrombin/fibrinogen depletion mechanism behind asparaginase thrombosis.PMIDTrend to efficacy and safety using antithrombin concentrate in prevention of thrombosis in children receiving l-asparaginase for acute lymphoblastic leukemia. Results of the PAARKA study.Mitchell L et al. · Thromb Haemost 2003 · PMID 12888870PARKAA RCT of antithrombin replacement to prevent thrombosis.PMIDAn antithrombin replacement strategy during asparaginase therapy for acute lymphoblastic leukemia is associated with a reduction in thrombotic events.Farrell K et al. · Leuk Lymphoma 2016 · PMID 27078747Antithrombin-replacement protocol associated with markedly fewer thrombotic events.PMIDProphylaxis of thromboembolism during therapy with asparaginase in adults with acute lymphoblastic leukaemia.Rank CU et al. · Cochrane Database Syst Rev 2020 · PMID 33038027Cochrane review on thromboprophylaxis (antithrombin, LMWH).PMIDRisk Factors for Asparaginase-associated Pancreatitis: A Systematic Review.Oparaji JA et al. · J Clin Gastroenterol 2017 · PMID 28375864Systematic review of pancreatitis (age, dose, PEG) — the other route to AKI.
Related agents
Other agents sharing the same signature kidney injury.