Doxorubicin
Adriamycin · Anthracycline
Experimental podocyte model; clinical proteinuria rare.
GLOM
MildOpen →
PD-1 x VEGF bispecific antibody
Ivonescimab
AK112 (Akeso/Summit) · PD-1×VEGF bispecific
Two nephrotoxic pathways in one molecule: VEGF-blockade glomerular injury plus checkpoint-inhibitor interstitial nephritis.
Moderate2020s targeted/immuno-angiogenic era · approved 2024
EGFR-mutated locally advanced/metastatic non-squamous NSCLC progressing after EGFR-TKI therapy (with pemetrexed + carboplatin; China approval May 2024)First-line PD-L1-positive advanced NSCLC (HARMONi-2, investigational/regional)First-line advanced squamous NSCLC with chemotherapy (HARMONi-6, investigational)
Signature kidney injury
Glomerular Injury / Proteinuria
Representative incidence3.1%
Renal-specific data are immature for this newly approved agent; no dedicated nephrotoxicity series exists. In registrational trials, grade >=3 VEGF-related adverse events (a class category encompassing proteinuria, hypertension, and hemorrhage) occurred in roughly 3% of patients (HARMONi-A: 5/161, 3.1%). Grade >=3 immune-related adverse events (the checkpoint-inhibitor category that includes AIN) occurred in ~6-9% across trials, though kidney-specific irAE rates were not separately tabulated. Clinically significant AKI was uncommon.
Source: HARMONi-A (JAMA 2024, PMID 38820549): grade >=3 VEGF-related AEs 3.1% (5/161); grade >=3 irAEs 6.2%. HARMONi-2 (Lancet 2025, PMID 40057343): grade >=3 irAEs 7%.
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
0%incidence
SeverityModerate
ReversibilityVariable
Evidence0 refs
Nephron map
GlomerulusFiltration barrier (podocytes + endothelium)
Vasculature / Endothelium
Interstitium
Glomerular Injury / Proteinuria
Damage to the filtration barrier — podocyte injury, FSGS and protein leak from VEGF and mTOR blockade.
Mechanism of kidney injury
Two convergent mechanisms. (1) VEGF-A sequestration removes podocyte-derived VEGF support of the glomerular filtration barrier, causing podocyte/endothelial dysfunction that manifests as proteinuria, VEGF-pathway hypertension (reduced nitric-oxide bioavailability, rarefaction), and rarely thrombotic microangiopathy - the same biology seen with bevacizumab and VEGF-TKIs. (2) PD-1/PD-L1 blockade can break renal immune tolerance and precipitate acute (granulomatous) interstitial nephritis, the canonical checkpoint-inhibitor kidney lesion. Direct tubular toxicity is not expected; pre-renal/hemodynamic contributions are minor.
Clinical presentation
Most commonly asymptomatic new or worsening proteinuria and rising blood pressure during therapy (VEGF effect). AIN presents as subacute creatinine rise weeks-to-months in, often with bland or sterile-pyuric sediment, sometimes eosinophilia; concurrent extrarenal irAEs are a clue. Nephrotic-range proteinuria, microangiopathic hemolysis (schistocytes, thrombocytopenia) suggest VEGF-mediated TMA and warrant drug hold.
Anticancer mechanism
Tetravalent humanized bispecific IgG that simultaneously blocks PD-1/PD-L1 (relieving T-cell immunosuppression) and sequesters VEGF-A (blocking VEGFR2-driven tumor angiogenesis). Co-targeting produces cooperative avidity-driven binding enriched in the VEGF-rich tumor microenvironment.
Management
VEGF-related proteinuria/hypertension: standard anti-VEGF algorithm - antihypertensives (ACEi/ARB preferred for proteinuria), dose interruption for nephrotic-range proteinuria or uncontrolled hypertension, discontinue for nephrotic syndrome or TMA. Suspected checkpoint-inhibitor AIN: hold the drug, exclude alternative causes, and treat with corticosteroids (e.g., prednisone ~0.5-1 mg/kg/day with taper) per immune-related AE guidelines; kidney biopsy when diagnosis is uncertain or response is inadequate. Nephrology co-management for persistent AKI, heavy proteinuria, or TMA.Lesion-level management framework
Risk factors
- Pre-existing hypertension or chronic kidney disease
- Baseline proteinuria
- Prior or concurrent anti-VEGF therapy (bevacizumab, VEGF-TKIs)
- Nephrotoxin co-exposure (platinum chemotherapy, NSAIDs, contrast)
- Prior immune-related adverse events on checkpoint inhibitors
- Diabetic or hypertensive nephropathy reducing renal reserve
Prevention
- Baseline and on-treatment urinalysis/UPCR and blood-pressure monitoring
- Optimize blood-pressure control before and during therapy
- Hold or dose-modify for >=2+ proteinuria or nephrotic-range proteinuria per VEGF-class precedent
- Maintain euvolemia and minimize concurrent nephrotoxins, especially with platinum doublets
- Baseline creatinine and periodic kidney-function checks
Note · According to PubMed, this profile is grounded in the ivonescimab registrational program. Renal toxicity is inferred from trial-reported VEGF-related and immune-related adverse-event categories plus VEGF-inhibitor/checkpoint-inhibitor class biology; no dedicated onconephrology case series was available at the time of writing. Key DOIs: HARMONi-A 10.1001/jama.2024.10613; HARMONi-2 10.1016/S0140-6736(24)02722-3; HARMONi-6 10.1016/S0140-6736(25)01848-3; First Approval 10.1007/s40265-024-02073-w.
Clinical depth
Renal dose adjustment
Dosed by weight (20 mg/kg IV every 3 weeks) as a monoclonal antibody; no pharmacokinetic renal dose adjustment is defined, and antibodies are not cleared by the kidney. Management is by holding/modifying for renal toxicity (proteinuria, hypertension, AIN) rather than by GFR-based dose reduction. No data in dialysis or severe CKD; use with nephrology input.
Dialyzability & ESKD dosing
Not dialyzable. As a ~150+ kDa IgG bispecific antibody, it is not removed by hemodialysis or peritoneal dialysis; timing of dosing around dialysis is irrelevant.
Differential diagnosis
Distinguish VEGF-pathway injury (proteinuria + hypertension, podocyte/endothelial) from checkpoint-inhibitor AIN (subacute creatinine rise, sterile pyuria, steroid-responsive) - the management diverges (drug hold/antihypertensives vs steroids). Also consider concurrent platinum (cisplatin/carboplatin) ATN, contrast-associated AKI, pre-renal azotemia from poor intake, and tumor-related obstruction. Microangiopathic hemolysis points to VEGF-mediated TMA rather than AIN.
Monitoring
- Urinalysis and urine protein-to-creatinine ratio (UPCR) at baseline and before each cycle
- Blood pressure at every visit and home monitoring
- Serum creatinine/eGFR with each cycle
- CBC and peripheral smear / LDH if TMA suspected
- Clinical surveillance for extrarenal immune-related adverse events
Key trials & series
- HARMONi-A (NCT05184712): ivonescimab + chemotherapy vs chemotherapy in EGFR-mutant TKI-relapsed NSCLC; basis of first approval (PMID 38820549)
- HARMONi-2 (NCT05499390): ivonescimab vs pembrolizumab in PD-L1+ first-line NSCLC, PFS 11.1 vs 5.8 months (PMID 40057343)
- HARMONi-6 (NCT05840016): ivonescimab + chemo vs tislelizumab + chemo in first-line squamous NSCLC (PMID 41125109)
- Phase 1a/1b dose-finding and first-in-human safety (PMID 38642937, 37879536)
Clinical pearls
- One molecule, two distinct renal mechanisms - read the urine: proteinuria + hypertension = VEGF arm; rising creatinine with sterile pyuria = checkpoint AIN arm. They are managed differently.
- VEGF-related grade >=3 AEs ran ~3% in the registrational trial; clinically meaningful AKI was uncommon - do not overstate direct nephrotoxicity.
- No GFR-based dose adjustment and not dialyzable - it is an IgG antibody, so renal handling does not drive dosing.
- Renal-specific literature is essentially absent for this 2024-approved frontier agent; the kidney profile is reasoned from VEGF-inhibitor and checkpoint-inhibitor class precedent plus trial AE categories.
- ACEi/ARB are first-line for VEGF-pathway proteinuria and hypertension; reserve corticosteroids for biopsy-supported or strongly suspected immune AIN.
Beyond the kidney
Class-level context for the major non-renal toxicities of pd-1 x vegf bispecific antibodys.
Vascular
Hypertension, VTE/ATE, bleeding, aneurysm
- Hypertension, arterial/venous thrombosis, bleeding, impaired wound healing
Cardiac
Cardiomyopathy, QT, ischemia, myocarditis
- LV dysfunction; QT (some TKIs)
Gastrointestinal
Diarrhea, colitis, mucositis, perforation
- Diarrhea, perforation/fistula
Dermatologic
Rash, HFS, SJS/TEN, vitiligo
- Hand-foot skin reaction
Evidence
5 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkIvonescimab Plus Chemotherapy in Non-Small Cell Lung Cancer With EGFR Variant: A Randomized Clinical Trial (HARMONi-A)Fang W et al. · JAMA 2024 · PMID 38820549Registrational phase 3 trial supporting first approval; reports grade >=3 VEGF-related AEs in 3.1% and grade >=3 immune-related AEs in 6.2% - the primary quantitative basis for the renal-risk estimate.PMIDIvonescimab versus pembrolizumab for PD-L1-positive non-small cell lung cancer (HARMONi-2): a randomised, double-blind, phase 3 study in ChinaXiong A et al. · Lancet 2025 · PMID 40057343Pivotal head-to-head phase 3 vs pembrolizumab; documents grade >=3 immune-related AEs (~7%) relevant to checkpoint-inhibitor AIN risk and overall safety profile.PMIDIvonescimab plus chemotherapy versus tislelizumab plus chemotherapy as first-line treatment for advanced squamous non-small-cell lung cancer (HARMONi-6): a randomised, double-blind, phase 3 trialChen Z et al. · Lancet 2025 · PMID 41125109Phase 3 squamous-NSCLC trial reporting VEGF-blockade-related toxicity (hemorrhage) and immune-related AE rates that frame the dual nephrotoxic mechanism.PMIDIvonescimab: First ApprovalDhillon S · Drugs 2024 · PMID 39073550Regulatory/mechanistic review summarizing the PD-1 x VEGF-A bispecific mechanism, dosing, and approval - the source for class framing and indication.PMIDPhase 1a dose escalation study of ivonescimab (AK112/SMT112), an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumorsFrentzas S et al. · Journal for ImmunoTherapy of Cancer 2024 · PMID 38642937First-in-human dose-finding and safety study establishing the early adverse-event spectrum, including VEGF-related events, for the bispecific.
Related agents
Other agents sharing the same signature kidney injury.