Busulfan
Myleran · Alkylator
Conditioning-regimen TMA risk.
TMA
ModerateOpen →
Nucleoside analog
Gemcitabine
Gemzar · Gem
The silent TMA — new hypertension months in is the warning sign.
SevereNucleoside analog · approved 1996
PancreaticBladderLungBreastOvarian
Signature kidney injury
Thrombotic Microangiopathy
Representative incidence1%
~0.015–2.2%; best single estimate ~0.31% cumulative. Historically high mortality.
Source: Walter et al., Am J Kidney Dis 2002
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeveritySevere
ReversibilityVariable
Evidence0 refs
Nephron map
GlomerulusFiltration barrier (podocytes + endothelium)
Vasculature / EndotheliumGlomerular & peritubular capillaries
Thrombotic Microangiopathy
Endothelial injury with microvascular thrombi, hemolysis and thrombocytopenia — gemcitabine, mitomycin C, anti-VEGF.
Mechanism of kidney injury
Direct, dose-cumulative glomerular endothelial toxicity creates microvascular thrombi, mechanically fragmenting red cells and consuming platelets. Median onset is ~8 months at cumulative doses of 9–56 g/m².
Clinical presentation
New or worsening hypertension (often the earliest sign), microangiopathic hemolytic anemia with schistocytes, thrombocytopenia, AKI and proteinuria.
Onset
Delayed — months of cumulative exposure.
Reversibility
Variable
Anticancer mechanism
Nucleoside analog incorporated into DNA, causing chain termination and inhibiting ribonucleotide reductase. Pancreatic, bladder, lung, breast and ovarian cancer.
Management
Discontinue gemcitabine (the key step), control BP, supportive care; eculizumab in refractory/severe cases. Plasma exchange is generally ineffective.
Risk factors
- High cumulative dose
- Prior mitomycin
- Hypertension
Prevention
- Monitor BP, CBC and creatinine
- No proven pharmacologic prophylaxis
Note · New hypertension during gemcitabine should trigger a TMA workup.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Glomerulus
Filtration barrier (podocytes + endothelium)
Injury signatures
Thrombotic MicroangiopathyHypertensionGlomerular Injury / Proteinuria
Beyond the kidney
Class-level context for the major non-renal toxicities of nucleoside 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
5 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkGemcitabine-associated hemolytic-uremic syndrome.Walter RB et al. · Am J Kidney Dis 2002 · PMID 12324937Pooled review defining the time course (~7 months / ~22 doses) and high mortality.PMIDReversible renal-limited thrombotic microangiopathy due to gemcitabine-dexamethasone-cisplatin therapy: a case report.Nishikubo M et al. · BMC Nephrol 2021 · PMID 33980166Renal-limited TMA reversible with drug cessation.PMIDGemcitabine-induced renal thrombotic microangiopathy.Horino T et al. · Nephrology (Carlton) 2022 · PMID 35429056Clinical illustration of renal TMA with AKI and nephrotic-range proteinuria.PMIDThrombotic microangiopathies and antineoplastic agents.Grangé S et al. · Nephrol Ther 2017 · PMID 28577731Distinguishes chemotherapy-induced from cancer-associated TMA.PMIDDrug-induced thrombotic microangiopathy: An updated review of causative drugs, pathophysiology, and management.Mazzierli T et al. · Front Pharmacol 2023 · PMID 36699080Comprehensive DITMA review and management.