Zenocutuzumab

Prerenal / Hemodynamic AKI.

Zenocutuzumab carries no meaningful direct renal signal and no discrete published incidence of drug-related acute kidney injury. In the registrational phase 2 eNRGy study (Schram, N Engl J Med 2025; n=204) adverse events were primarily grade 1 or 2, the most common treatment-related events were diarrhea (18%), fatigue (12%), and nausea (11%), infusion-related reactions occurred in 14%, and only one patient discontinued for a treatment-related event. The only renal-relevant route is indirect: diarrhea and, less often, infusion reactions can produce volume depletion and prerenal physiology if significant. Unlike T-cell-engaging bispecifics, this HER2xHER3 antibody does not carry a cytokine-release or tumor-lysis mechanism, so it lacks that class's renal hazards.

Source: No direct renal signal; mostly grade 1-2 AEs with diarrhea 18% (eNRGy, Schram 2025); at most diarrhea-related prerenal risk, no CRS/TLS mechanism

Reported injury signatures: Prerenal / Hemodynamic AKI, Electrolyte Disturbance.

1. Prerenal / Hemodynamic AKIPrimary
2. Electrolyte DisturbanceSecondary

Acute (~1–7 days) — No direct renal onset; infusion-related effects are hyperacute (during/around the infusion), and diarrhea-related prerenal physiology, if it occurs, follows the diarrheal episodes across treatment.

• Significant or poorly controlled diarrhea (the main prerenal driver)
• Infusion-related reactions with hypotension
• Baseline CKD or volume depletion
• Concurrent nephrotoxins or diuretics
• Poor oral intake during GI toxicity

• Manage diarrhea early (antidiarrheals, hydration) to prevent volume depletion
• Use infusion-reaction precautions/premedication per protocol and monitor during infusions
• Encourage hydration; give IV fluids when intake is inadequate
• Monitor renal function and electrolytes during treatment
• Review and minimize concurrent nephrotoxins

• Diarrhea frequency/severity and volume status (the primary indirect renal-risk driver)
• Vital signs during infusions for infusion-related reactions/hypotension
• Serum creatinine/eGFR and electrolytes during treatment
• Potassium if diarrhea is significant

• eNRGy (Schram, N Engl J Med 2025) — registrational phase 2 study of zenocutuzumab in NRG1-fusion-positive cancers (n=204; 12 tumor types); responses in 30% overall (including NSCLC and pancreatic cancer) with adverse events primarily grade 1-2 — diarrhea 18%, fatigue 12%, nausea 11%, infusion-related reactions 14% — and only one treatment-related discontinuation, defining a tolerability profile with, at most, indirect (prerenal) renal risk.
• Acute kidney injury with cancer immunotherapy (Joseph, Cells 2022) — reviews the AKI mechanisms of T-cell-engaging bispecifics (cytokine release, tumor lysis); a useful contrast showing why a HER2xHER3 antibody like zenocutuzumab, which does not engage T cells, lacks those renal hazards.

• Not that kind of bispecific: zenocutuzumab blocks HER2-HER3 dimerization and does not engage T cells, so it lacks the cytokine-release/tumor-lysis AKI of CD3 engagers.
• Its only real route to the kidney is diarrhea (18%) — manage the diarrhea and you manage the prerenal risk.
• Watch infusions: a reaction with hypotension is a transient prerenal insult that resolves with perfusion support.
• A large IgG1 antibody is not dialyzable and not renally cleared — GFR doesn't change its dosing.
• A creatinine rise here is volume, not tubular poisoning — rehydrate and reassess.

• TLS Expert Panel (2008) — Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based reviewPrevention is the best management: hydration plus prophylactic rasburicase for high-risk patients, hydration plus allopurinol or rasburicase for intermediate-risk, and monitoring for low-risk; for established TLS add aggressive hydration and diuresis plus allopurinol or rasburicase for hyperuricemia. Urinary alkalinization is NOT recommended.J Clin Oncol · PMID 18509186
• TLS Consensus Panel (2010) — Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensusStratify each patient as low/intermediate/high TLS risk using tumor type, bulk/stage, proliferation rate, baseline laboratory TLS, and renal impairment/involvement, then match prophylaxis intensity (monitoring vs allopurinol vs rasburicase) to the assigned risk level.Br J Haematol · PMID 20331465
• BCSH (2015) — Guidelines for the management of tumour lysis syndrome in adults and children with haematological malignancies on behalf of the British Committee for Standards in HaematologyRisk-adapted prophylaxis and management of TLS in haematological malignancy: hydration with allopurinol for lower-risk and rasburicase for high-risk patients, with monitoring of electrolytes and renal function to prevent and treat AKI.Br J Haematol · PMID 25876990
• Cairo-Bishop (2004) — Tumour lysis syndrome: new therapeutic strategies and classificationDefines the Cairo-Bishop criteria distinguishing laboratory TLS (>=2 metabolic abnormalities: hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia within 3 days before to 7 days after therapy) from clinical TLS (laboratory TLS plus AKI, cardiac arrhythmia, or seizure), with a severity grading scheme adopted by subsequent guidelines.Br J Haematol · PMID 15384972
• ASTCT (2019) — ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector CellsGrade CRS by fever, hypotension and hypoxia (grades 1-4) and grade ICANS using the ICE/encephalopathy score plus level of consciousness, seizures, motor findings and raised intracranial pressure/edema; this is the standard severity framework that triggers tocilizumab and corticosteroid escalation in CAR-T and bispecific antibody toxicity (the Lee 2019 consensus).Biol Blood Marrow Transplant · PMID 30592986
• 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 (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