Ramucirumab
Cyramza · Anti-VEGFR2 antibody
Hypertension and proteinuria, class effect.
HTNGLOMTMA
ModerateOpen →
RET inhibitor
Selpercatinib
Retevmo · Selp
A selective RET inhibitor whose cardiometabolic signature includes hypertension and creatinine rise.
ModerateRET inhibitor · approved 2020
RET fusion-positive NSCLCRET fusion-positive thyroid cancerRET-mutant medullary thyroid cancer
Signature kidney injury
Hypertension
Hypertension is among the most common adverse events in LIBRETTO-001 (a frequent grade >=3 event), and a reversible serum-creatinine increase is also recognized. A single-center hereditary-MTC series found hypertension in ~26% on selective RET inhibitors.
Source: Drilon et al., N Engl J Med 2020
Mechanism of kidney injury
Hypertension is an on/near-target vascular effect of RET-pathway inhibition (with endothelial/nitric-oxide and vascular-tone contributions shared by many kinase inhibitors). The creatinine rise is thought to reflect, at least in part, inhibition of tubular creatinine secretion (pseudo-AKI) rather than true GFR decline, although hemodynamic (hypertension-mediated) effects may contribute.
Clinical presentation
New or worsened hypertension; mild reversible creatinine elevation without active sediment, with a stable cystatin C-based eGFR in the transporter-mediated cases. QT prolongation and transaminitis are other class effects to monitor.
Onset
Hypertension within the first weeks to months; creatinine changes early.
Reversibility
Reversible
Anticancer mechanism
Highly selective RET kinase inhibitor active against RET fusions and activating mutations; approved for RET fusion-positive NSCLC and thyroid cancers and RET-mutant medullary thyroid cancer.
Management
Standard antihypertensive therapy (and lifestyle measures); dose-interrupt then reduce for medically uncontrolled BP, and hold for severe/refractory hypertension. Isolated creatinine rise usually warrants monitoring and a cystatin C check; evaluate for true AKI if progressive or accompanied by proteinuria/active sediment.
Risk factors
- Pre-existing hypertension
- Cardiovascular disease
- Concurrent nephrotoxins or QT-prolonging drugs
Prevention
- Baseline and regular blood-pressure monitoring
- Optimize antihypertensives before/during therapy
- Periodic creatinine checks; cystatin C if GFR change is ambiguous
Note · Creatinine rise may overstate true GFR loss (transporter effect); hypertension is the principal renal-relevant signal.
Clinical depth
Renal dose adjustment
No dose adjustment for mild-moderate renal impairment; severe impairment is not well characterized and dialysis is not studied (use with caution). Weight-based dosing; modifications are driven by hypertension, QTc, hepatotoxicity, and hemorrhage.
Dialyzability & ESKD dosing
Highly protein-bound oral small molecule; not expected to be appreciably dialyzed. No validated ESKD dosing.
Differential diagnosis
Drug-induced hypertension vs essential/secondary causes; transporter-mediated pseudo-AKI (stable cystatin C, bland urine) vs true AKI (prerenal from poorly controlled BP, ATN, or AIN). A flat cystatin C with a creatinine bump indicates the transporter effect.
Monitoring
- Blood pressure at baseline, after 1 week, at least monthly, and as clinically indicated
- Serum creatinine periodically; cystatin C-based eGFR if a true GFR change is suspected
- ECG/QTc and liver enzymes per label
Key trials & series
- LIBRETTO-001 (RET fusion-positive NSCLC and thyroid; RET-mutant MTC)
- LIBRETTO-431 (first-line RET fusion-positive NSCLC)
- Hamidi 2024 hereditary-MTC RET-inhibitor safety series
Clinical pearls
- Treat the blood pressure and check a cystatin C before assuming the creatinine rise means true GFR loss.
- Hypertension is the principal renal-relevant signal — manage it to keep patients on effective RET-directed therapy.
- Co-monitor QTc, since selective RET inhibitors prolong it and several antihypertensive/antiemetic co-medications also do.
Where it strikes
Nephron segments
Vasculature / Endothelium
Glomerular & peritubular capillaries
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
HypertensionPrerenal / Hemodynamic AKI
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkEfficacy of Selpercatinib in RET Fusion-Positive Non-Small-Cell Lung Cancer.Drilon A et al. · N Engl J Med 2020 · PMID 32846060Pivotal LIBRETTO-001 NSCLC results listing hypertension among the most common adverse events.PMIDTumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial.Subbiah V et al. · Lancet Oncol 2022 · PMID 36108661Basket-trial safety data including hypertension across tumor types.PMIDEfficacy and Safety of Selective RET Inhibitors in Patients with Advanced Hereditary Medullary Thyroid Carcinoma.Hamidi S et al. · Thyroid 2024 · PMID 39630530Single-center hMTC series quantifying hypertension (~26%) and other AEs with selpercatinib/pralsetinib.PMIDTargeted Cancer Therapies Causing Elevations in Serum Creatinine Through Tubular Secretion Inhibition: A Case Report and Review of the Literature.Mach T et al. · Can J Kidney Health Dis 2022 · PMID 35756332Supports a transporter-mediated (pseudo-AKI) interpretation of TKI creatinine elevation, confirmable with cystatin C.PMIDNavigating the Complexities of Cancer Treatment-Induced Hypertension.Arriola-Montenegro J et al. · J Cardiovasc Dev Dis 2025 · PMID 40558670Reviews mechanisms and management of kinase-inhibitor-associated hypertension.PMIDCurrent Trends in Anti-Cancer Molecular Targeted Therapies: Renal Complications and Their Histological Features.Tonooka A et al. · J Nippon Med Sch 2021 · PMID 34840210Onconephrology review of TKI-associated renal and vascular complications.
Related agents
Other agents sharing the same signature kidney injury.