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JAK/ACVR1 inhibitor

Momelotinib

Ojjaara · MOME

JAK/ACVR1 inhibitor · approved 2023 · 7 references

A JAK1/2 plus ACVR1 inhibitor for anemic myelofibrosis whose characteristic renal signal is a frequent, low-grade creatinine rise without true GFR loss.

Signature injury
Pseudo-AKI
Severity
Mild
Reversibility
Reversible
Onset
Any tumor-lysis risk is early; otherwise no defined renal onset.

Signature kidney injury & incidence

Pseudo-AKI — representative incidence ~29% (17–29% range across studies).

Treatment-emergent 'nephropathy' — a predominantly low-grade, isolated serum-creatinine rise — is now a recognized and frequent momelotinib signal, reported in ~17-29% across real-world cohorts (~29% in first-line real-world use; ~17% CTCAE grade 1-2 creatinine increase in a retrospective real-world cohort). Momelotinib pharmacokinetics are unchanged across renal impairment, arguing the creatinine rise reflects altered tubular handling rather than a true GFR fall (a pseudo-AKI). Tumor-lysis at initiation in high-burden disease remains a separate, indirect risk.

Source: Tefferi et al., Am J Hematol 2026

Reported injury signatures: Pseudo-AKI, Prerenal / Hemodynamic AKI.

Renal toxicity profile

  1. Pseudo-AKIPrimary
  2. Prerenal / Hemodynamic AKISecondary

Onset timing & rechallenge

Variable / unpredictable — Any tumor-lysis risk is early, but otherwise there is no defined renal onset.

Mechanism of kidney injury

The defining renal event is a frequent, mostly low-grade isolated creatinine elevation without evidence of true GFR loss — momelotinib exposure is unchanged in moderate-to-severe renal impairment — consistent with interference in tubular creatinine handling (a pseudo-AKI) rather than structural nephron injury. The ACVR1/hepcidin mechanism targets systemic iron metabolism, not the kidney. A separate, indirect prerenal/tumor-lysis risk applies at initiation in high-burden disease.

Clinical presentation

Typically an isolated, low-grade serum-creatinine rise emerging on treatment with an otherwise bland urinalysis and stable clinical picture; checking a cystatin C-based eGFR helps confirm preserved true GFR before attributing it to structural injury. Early metabolic derangements if tumor lysis occurs at initiation.

Management

Supportive; tumor-lysis management if it occurs, treat infection, correct prerenal factors. No drug-specific renal therapy; intrinsic nephrotoxicity has not been established.

Risk factors

  • High-burden myelofibrosis (TLS risk at initiation)
  • Pre-existing CKD
  • Infection/cytopenia-related volume depletion

Prevention

  • TLS awareness/hydration at initiation in high-burden disease
  • Renal-appropriate dosing per label

Renal dose adjustment

No dose adjustment is needed for mild-to-severe renal impairment per the registrational program; momelotinib is hepatically metabolized (with an active metabolite). Data in dialysis are limited. Dose modification is driven primarily by cytopenias rather than renal function.

Dialyzability & ESKD dosing

Not characterized; highly protein-bound, hepatically cleared. Not expected to be meaningfully dialyzed. No ESKD-specific dosing guidance.

Differential diagnosis

Distinguish the frequent isolated low-grade creatinine rise (pseudo-AKI: bland urinalysis, preserved cystatin C-based eGFR) from early tumor-lysis AKI, infection/cytopenia-related prerenal AKI, and unrelated intrinsic renal disease; structural nephrotoxicity is not established.

Monitoring

  • CBC with platelets (dose-limiting thrombocytopenia)
  • Creatinine, electrolytes and uric acid at initiation in high-burden disease
  • Peripheral neuropathy assessment and infection/HBV reactivation surveillance
  • Serum creatinine and electrolytes periodically on therapy, not only at initiation

Key trials & series

  • MOMENTUM and SIMPLIFY-1 — registrational myelofibrosis-with-anemia trials (clinical context)

Clinical pearls

  • Momelotinib's distinguishing trick is lowering hepcidin (ACVR1) to improve anemia — a non-renal mechanism.
  • Watch for peripheral neuropathy, a class-distinct momelotinib toxicity.
  • The common renal event is an isolated low-grade creatinine rise without true GFR loss — a pseudo-AKI, not a reason to dose-reduce.

Anticancer mechanism

Oral inhibitor of JAK1/JAK2 and ACVR1 (ALK2). ACVR1 inhibition lowers hepcidin via the BMP6/ACVR1/SMAD axis, increasing iron availability and improving anemia — distinguishing it from other JAK inhibitors. Approved for intermediate/high-risk myelofibrosis with anemia.

Note

2023 approval. Treatment-emergent nephropathy — an isolated low-grade creatinine rise — is now documented in real-world cohorts (Tefferi 2026; Jilg 2024), and unchanged pharmacokinetics across renal impairment support a tubular pseudo-AKI rather than true GFR loss. The prerenal/TLS framing remains indirect class reasoning.

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

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

  1. 1.Post-FDA Approval Experience With Momelotinib in JAK Inhibitor-Naive Myelofibrosis: Focus on Anemia Response and Treatment-Emergent Nephropathy and Peripheral Neuropathy.Tefferi A et al. · Am J Hematol · 2026 · PMID 41504170
  2. 2.MoReLife - real-life data support the potential of momelotinib as a safe and effective treatment option for cytopenic myelofibrosis patients.Jilg S et al. · Ann Hematol · 2024 · PMID 39073589
  3. 3.Pharmacokinetics and Safety of Momelotinib in Subjects With Hepatic or Renal Impairment.Xin Y et al. · J Clin Pharmacol · 2017 · PMID 29283448
  4. 4.ACVR1: A Novel Therapeutic Target to Treat Anemia in Myelofibrosis.Duminuco A et al. · Cancers (Basel) · 2023 · PMID 38201581
  5. 5.Acute Kidney Injury in Patients With Cancer: A Review of Onconephrology.Gudsoorkar P et al. · Adv Chronic Kidney Dis · 2021 · PMID 35190106
  6. 6.Tumor Lysis Syndrome.Barbar T et al. · Adv Chronic Kidney Dis · 2021 · PMID 35190110
  7. 7.New drug toxicities in the onco-nephrology world.Perazella MA et al. · Kidney Int · 2015 · PMID 25671763
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.