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Anti-Claudin-18.2 monoclonal antibody

Zolbetuximab

Vyloy · Zolb

Anti-Claudin-18.2 monoclonal antibody · approved 2024 · 4 references

A Claudin-18.2 antibody whose renal risk is indirect — severe nausea and vomiting driving prerenal AKI.

Signature injury
Prerenal / Hemodynamic AKI
Severity
Moderate
Reversibility
Reversible
Onset
Around infusions, especially the first cycles, tracking the nausea/vomiting peak.

Signature kidney injury & incidence

Prerenal / Hemodynamic AKI.

Direct nephrotoxicity is not a recognized feature. The defining, dose-limiting toxicity in the pivotal SPOTLIGHT and GLOW trials is severe nausea and vomiting (an on-target effect on gastric mucosa), which can cause volume depletion and prerenal acute kidney injury. A quantified renal-injury rate is not reported; the renal risk is mechanistic/indirect.

Source: Shah et al., Nat Med 2023 (GLOW); nausea/vomiting-driven volume depletion

Reported injury signatures: Prerenal / Hemodynamic AKI.

Onset timing & rechallenge

Acute (~1–7 days) — Prerenal AKI around infusions, especially the first cycles, tracking the nausea/vomiting peak.

Mechanism of kidney injury

Claudin-18.2 is also expressed in normal gastric mucosa, so zolbetuximab provokes prominent nausea and vomiting, especially with the first infusions. The resulting fluid and electrolyte losses cause hypovolemia and a prerenal/hemodynamic AKI; sustained hypovolemia can progress to ischemic tubular injury. There is no characteristic intrinsic tubular or glomerular lesion attributable to the antibody itself, and it is not renally cleared.

Clinical presentation

A prerenal creatinine rise in the context of severe nausea/vomiting with clinical volume depletion (orthostasis, low urine output, high BUN:creatinine ratio), typically around infusions. Electrolyte disturbances from vomiting (hypokalemia, metabolic alkalosis) may accompany it.

Management

Volume resuscitation and antiemetics for prerenal AKI; reduce infusion rate or interrupt for severe nausea/vomiting per label. Correct vomiting-related electrolyte disturbances. Injury is generally reversible with timely volume repletion; coordinate with concurrent platinum nephrotoxicity management.

Risk factors

  • Severe nausea/vomiting (drug-specific, on-target)
  • Inadequate antiemetic prophylaxis
  • Pre-existing CKD
  • Concurrent nephrotoxic chemotherapy (platinum) and volume depletion

Prevention

  • Aggressive antiemetic prophylaxis (including infusion-rate reduction/interruption)
  • Hydration around infusions
  • Coordinate with platinum-chemotherapy hydration protocols

Renal dose adjustment

No dedicated renal dose adjustment is established; mild–moderate impairment does not require change and severe impairment/ESKD are not well studied. Management is antiemetic control and volume repletion rather than fixed renal dosing.

Dialyzability & ESKD dosing

The IgG1 antibody is not dialyzable and is cleared by proteolysis; no ESKD dose change is defined. Dialysis would support AKI management, not drug removal.

Differential diagnosis

Prerenal AKI from nausea/vomiting volume loss (hypovolemia, fluid-responsive) vs concurrent platinum-chemotherapy tubular injury (ATN) vs unrelated intrinsic renal disease; zolbetuximab has no characteristic renal lesion of its own, and the vomiting time-course is the clue.

Monitoring

  • Nausea/vomiting severity and volume status around infusions
  • Coordinate with platinum-chemotherapy renal monitoring

Key trials & series

  • GLOW (Shah Nat Med 2023) — pivotal phase 3 with CAPOX
  • SPOTLIGHT — pivotal phase 3 with mFOLFOX6 (overall context)

Clinical pearls

  • Control the vomiting, protect the kidney: zolbetuximab's renal risk is volume depletion from on-target gastric-mucosa nausea/vomiting.
  • It is usually given with platinum chemotherapy — separate the prerenal (vomiting) and tubular (platinum) contributions.

Anticancer mechanism

Chimeric IgG1 monoclonal antibody targeting Claudin-18.2, a tight-junction protein exposed on gastric and gastroesophageal adenocarcinoma cells. Binding triggers antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Given with chemotherapy (e.g., CAPOX/mFOLFOX6) for CLDN18.2-positive, HER2-negative locally advanced/metastatic gastric or GEJ adenocarcinoma.

Note

No zolbetuximab-specific renal study exists; the renal concern is indirect (severe nausea/vomiting to volume depletion to prerenal AKI), drawn from pivotal-trial adverse-event data. Treat prerenal AKI as a mechanistic inference, not a directly reported endpoint.

Guidelines & consensus

Each recommendation below is this atlas's faithful summary of the source, not a quotation from it — follow the PubMed link for the wording the society published. Summaries may be superseded; consult the current full text and individualize to the patient.

  • ADQI (2026) — The nephrotoxic effects of anti-cancer therapies: consensus report of the 34th Acute Disease Quality Initiative workgroupProvides expert-based statements (modified Delphi) on preventing and managing cisplatin/platinum-associated AKI, including isotonic IV hydration, attention to volume status and concomitant nephrotoxins, and incorporates evidence that IV magnesium supplementation may reduce cisplatin-associated AKI; emphasizes risk stratification and standardized AKI definitions.Nat Rev Nephrol · PMID 41361704
  • SIRM (2022) — SIRM-SIN-AIOM: appropriateness criteria for evaluation and prevention of renal damage in the patient undergoing contrast medium examinations-consensus statements from Italian College of Radiology (SIRM), Italian College of Nephrology (SIN) and Italian Association of Medical Oncology (AIOM)Recommends eGFR-based renal risk assessment and pre/post-contrast isotonic saline or sodium bicarbonate hydration; advises maintaining a 5-7 day interval between iodinated contrast administration and cisplatin in cancer patients to reduce additive nephrotoxicity.Radiol Med · PMID 35303246
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: understanding kidney impairment and solid-organ malignancies, and managing kidney cancerIdentifies platinum compounds (especially cisplatin) as leading cytotoxic causes of acute tubular injury, AKI, and electrolyte/magnesium wasting; calls for interdisciplinary onco-nephrology care, accurate GFR estimation, and individualized drug dosing in patients with reduced kidney function.Kidney Int · PMID 33126977
  • KDIGO (2020) — KDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantationAddresses chemotherapy-associated AKI/CKD in hematologic cancer, GFR estimation and chemotherapy dosing in patients with reduced kidney function, and management priorities and research gaps for onco-nephrology care.Kidney Int · PMID 33276867
  • ADDIKD (2025) — Integrating International Consensus Guidelines for Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) into everyday practiceProvides GRADE-based, drug-specific dose-adjustment recommendations for anticancer agents in kidney dysfunction (illustrated for methotrexate, cisplatin, carboplatin and nivolumab); the recommendations build on Part 1's standardised CKD-EPI eGFR assessment rather than Cockcroft-Gault creatinine clearance.EClinicalMedicine · PMID 40290844
  • ADDIKD (2025) — Aligning kidney function assessment in patients with cancer to global practices in internal medicineThree consensus recommendations: assess kidney function by GFR (measured GFR or CKD-EPI eGFR), classify it using KDIGO categories, and use this uniform approach to dose anticancer drugs — moving cancer medicine away from Cockcroft-Gault estimated creatinine clearance.EClinicalMedicine · PMID 40290845
  • ADDIKD (2025) — A methodology for determining dosing recommendations for anticancer drugs in patients with reduced kidney functionEstablishes that, where RCT evidence is lacking, anticancer drug dosing recommendations in kidney dysfunction should be derived by critically appraising observational literature via GRADE combined with structured international multidisciplinary consensus voting.EClinicalMedicine · PMID 40290846
  • KDIGO (2013) — Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1)Defines/stages AKI by serum creatinine and urine output; emphasizes avoiding nephrotoxins, maintaining euvolemia/perfusion, dose-adjusting drugs to kidney function, and monitoring high-risk patients — the framework applied to nephrotoxic anti-cancer agents.Crit Care · PMID 23394211
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease: known knowns and known unknownsEvaluate and risk-stratify CKD, manage to delay progression and its complications, and practise explicit medication management and drug stewardship — the framework the atlas's G1–G5 eGFR banding and every renal dose-adjustment recommendation sit inside. Because the guideline excludes dialysis and transplant recipients by its own statement of scope, its recommendations do not carry to those settings, where this atlas's dialyzability and post-transplant guidance rests on other sources.Kidney Int · PMID 38519239
  • KDIGO (2021) — Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular DiseasesProvides the staging/treatment framework for drug-associated glomerular lesions (e.g., bisphosphonate- and interferon-related collapsing FSGS, VEGF-inhibitor podocytopathy/proteinuria), including immunosuppression and supportive RAAS-blockade strategies.Kidney Int · PMID 34556300
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of ANCA-Associated VasculitisUpdates immunosuppressive induction (rituximab/cyclophosphamide), incorporates avacopan and lower-dose or glucocorticoid-sparing regimens — the management framework for drug- and checkpoint-inhibitor-associated ANCA/pauci-immune glomerulonephritis.Kidney Int · PMID 38388147
  • KDIGO (2024) — Executive summary of the KDIGO 2024 Clinical Practice Guideline for the Management of Lupus NephritisUpdates first-line lupus nephritis therapy to combination immunosuppression with the addition of belimumab or a calcineurin inhibitor (voclosporin) — informs management of immune-complex/lupus-like glomerulonephritis encountered with immunotherapy.Kidney Int · PMID 38182299
  • KDIGO (2025) — Executive summary of the KDIGO 2025 Clinical Practice Guideline for the Management of Immunoglobulin A Nephropathy (IgAN) and Immunoglobulin A Vasculitis (IgAV)Encourages liberal kidney biopsy and stricter proteinuria control (<0.5 g/d, ideally <0.3 g/d) with RAAS blockers, SGLT2 inhibitors, and targeted-release budesonide — the framework for IgA-dominant glomerular lesions, including those triggered by immune-modulating cancer therapy.Kidney Int · PMID 40975525

References

4 peer-reviewed references. Citation metadata via PubMed / NLM.

  1. 1.Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial.Shah MA et al. · Nat Med · 2023 · PMID 37524953
  2. 2.SPOTlight on GLOW.Derks S et al. · Cell Rep Med · 2023 · PMID 37852180
  3. 3.Zolbetuximab-clzb: Targeting Claudin 18.2 in Advanced Gastric and Gastroesophageal Adenocarcinoma.Gorwitz GL et al. · Ann Pharmacother · 2025 · PMID 40426305
  4. 4.Renal Side Effects of Novel Molecular Targeted Oncologic Agents.Fenoglio R et al. · G Ital Nefrol · 2023 · PMID 38007829
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.