Bendamustine
Treanda · Alkylator
Tumor lysis-mediated AKI is the principal risk; TMA is rare.
PRETMALYTE
ModerateOpen →
PI3Kδ/γ inhibitor
Duvelisib
Copiktra · DUV
Dual PI3K-delta/gamma inhibitor with the same immune-colitis Achilles heel — diarrhea and volume loss are the path to prerenal AKI.
MildDual-isoform PI3K inhibitor · approved 2018
Relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (>=2 prior therapies)Relapsed/refractory follicular lymphoma (historically; indication later narrowed)
Signature kidney injury
Prerenal / Hemodynamic AKI
Diarrhea/colitis is common (any-grade ~50%, grade 3+ roughly 15-20% in DUO); the resulting volume-depletion prerenal AKI is not separately tabulated. Direct nephrotoxicity is uncommon.
Source: Flinn et al., Blood 2018 (DUO); Flinn et al., J Clin Oncol 2019 (DYNAMO)
Mechanism of kidney injury
As with idelalisib, PI3K-delta/gamma inhibition impairs regulatory T-cell tolerance and produces immune-mediated colitis, hepatitis and pneumonitis. The PI3K-gamma component adds effects on myeloid/innate immunity. Renal injury is secondary — secretory diarrhea and reduced intake cause volume contraction and prerenal azotemia, with ischemic ATN possible if hypoperfusion is severe and prolonged; immune-mediated interstitial nephritis is plausible but not a defining feature.
Clinical presentation
Profuse, sometimes late-onset diarrhea or frank colitis, dehydration and orthostasis; creatinine rises with a prerenal urine profile (low FeNa, high urine osmolality). Transaminitis, rash and pneumonitis may coexist as part of the immune toxicity.
Onset
Diarrhea/colitis often after several months; rash and transaminitis can appear earlier.
Reversibility
Reversible
Anticancer mechanism
Oral dual inhibitor of the delta and gamma isoforms of PI3K. PI3K-delta drives malignant B-cell proliferation while PI3K-gamma modulates the supportive tumor microenvironment; combined inhibition is active in CLL/SLL and follicular lymphoma.
Management
Interrupt duvelisib for severe diarrhea/colitis, exclude infectious causes, rehydrate, and treat immune colitis with corticosteroids (budesonide or systemic steroids). Restore euvolemia to reverse prerenal AKI; consider AIN with steroid trial if creatinine fails to recover despite volume repletion. Permanently discontinue for life-threatening events.
Risk factors
- Pre-existing CKD, diuretic therapy or baseline volume depletion
- Concurrent nephrotoxins
- Older age and frailty
- Delayed recognition of severe diarrhea
Prevention
- Early reporting and prompt management of diarrhea; exclude infection (including CMV)
- Vigorous rehydration during diarrheal episodes
- Infection prophylaxis (PJP; CMV monitoring) per label
- Interrupt for grade 3+ diarrhea/colitis
Note · Renal involvement is indirect, mediated by immune colitis/diarrhea and volume depletion. Quantified AKI rates are lacking; the signal is inferred from the dominant GI toxicity.
Clinical depth
Renal dose adjustment
No renal dose adjustment specified (hepatic CYP3A4 metabolism); use caution in CKD. Dose modifications are driven by colitis, hepatotoxicity, infection and cytopenias.
Dialyzability & ESKD dosing
Highly protein-bound; not expected to be dialyzable. No ESKD dosing established.
Differential diagnosis
Separate prerenal AKI (volume-responsive, low FeNa) from infectious colitis (C. difficile, CMV) driving the losses and from immune AIN; concurrent hepatotoxicity can confound with hepatorenal physiology.
Monitoring
- Stool frequency and volume status; weight at each visit
- LFTs every 2 weeks initially, then periodically
- Serum creatinine/electrolytes during diarrheal episodes
- Infection surveillance with PJP prophylaxis and CMV monitoring
Key trials & series
- DUO (Flinn, Blood 2018) — registrational RCT vs ofatumumab defining the colitis/diarrhea signal
- DYNAMO (Flinn, J Clin Oncol 2019) — indolent NHL safety dataset
Clinical pearls
- Mechanistically and clinically a sibling of idelalisib — anticipate immune colitis and dehydration.
- Late-onset severe diarrhea is the classic and most dangerous toxicity; rehydrate early.
- Exclude CMV before attributing colitis to the drug and starting steroids.
- PJP prophylaxis and CMV vigilance are part of standard care.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Interstitium
Supporting tissue around the tubules
Injury signatures
Prerenal / Hemodynamic AKIAcute Interstitial Nephritis
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkThe phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL.Flinn IW et al. · Blood 2018 · PMID 30287523Registrational RCT establishing efficacy and the diarrhea/colitis toxicity that drives prerenal injury.PMIDDYNAMO: A Phase II Study of Duvelisib in Patients With Refractory Indolent Non-Hodgkin Lymphoma.Flinn IW et al. · J Clin Oncol 2019 · PMID 30742566Indolent NHL safety dataset including GI toxicity profile.PMIDManagement of toxicities associated with PI3K inhibitors in hematologic malignancies.Hanlon A et al. · Hematology Am Soc Hematol Educ Program 2020 · PMID 33275709Practical management of class colitis/diarrhea/hepatotoxicity relevant to renal volume status.PMIDDuvelisib for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma.Frustaci AM et al. · Future Oncol 2019 · PMID 31137964Clinical review of efficacy and toxicity management.PMIDPI3K inhibitors in hematologic malignancies.Shouse G et al. · Curr Opin Oncol 2022 · PMID 35855508Class-level perspective on immune-mediated toxicities and their management.PMIDDuvelisib, a PI3K-delta/gamma inhibitor, in patients with relapsed/refractory lymphoma.Faia K et al. · PLoS One 2018 · PMID 30067771Pharmacology supporting the dual delta/gamma mechanism and toxicity rationale.
Related agents
Other agents sharing the same signature kidney injury.