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JAK1/2 inhibitor

Ruxolitinib

Jakafi · RUXO

JAK1/2 inhibitor · approved 2011 · 5 references

A JAK1/2 inhibitor for myelofibrosis whose kidney risks are tumor-lysis and dose-adjustment, not direct toxicity.

Signature injury
Prerenal / Hemodynamic AKI
Severity
Mild
Reversibility
Reversible
Onset
Any tumor-lysis risk is early (first cycles); withdrawal syndrome occurs within days of stopping; otherwise no defined renal onset.

Signature kidney injury & incidence

Prerenal / Hemodynamic AKI.

No established intrinsic nephrotoxicity. Over a decade of safety data show cytopenias and infections (including opportunistic) as the dominant toxicities. Renal concerns are indirect: rare tumor-lysis at treatment initiation in bulky myelofibrosis, the need for dose reduction in renal impairment, and a recognized ruxolitinib-withdrawal syndrome on abrupt cessation — rather than direct tubular injury.

Source: Verstovsek et al., J Hematol Oncol 2023

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

Renal toxicity profile

  1. Prerenal / Hemodynamic AKIPrimary
  2. Electrolyte DisturbanceSecondary
  3. Thrombotic MicroangiopathyRareIndependent predictor of transplant-associated TMA in a GVHD cohort; a transplant-context signal.

Onset timing & rechallenge

Variable / unpredictable — Tumor-lysis risk is confined to the first cycles and a withdrawal syndrome occurs within days of stopping, but otherwise there is no defined renal onset.

Mechanism of kidney injury

No characterized direct nephron injury. Plausible renal stress is indirect: tumor-lysis-type metabolic derangements early after starting therapy in high-burden disease (urate/phosphate intratubular deposition), infection/cytopenia-related complications causing prerenal/ischemic AKI, and a ruxolitinib-withdrawal syndrome (cytokine rebound with hemodynamic instability, occasionally a capillary-leak-like picture) on abrupt discontinuation.

Clinical presentation

Usually a bland renal picture; if tumor lysis occurs, hyperuricemia/hyperphosphatemia with creatinine rise; prerenal AKI in the setting of infection or volume depletion; abrupt-withdrawal symptom flare with hemodynamic compromise.

Management

Supportive; standard tumor-lysis management if it occurs, treat infections, correct prerenal factors, and adjust dose for renal function. For withdrawal syndrome, resume ruxolitinib and provide hemodynamic support. No drug-specific renal therapy; intrinsic nephrotoxicity has not been established.

Risk factors

  • Bulky/high-burden myelofibrosis (TLS risk at initiation)
  • Pre-existing CKD (requires dose adjustment)
  • Infection and cytopenia-related volume depletion
  • Abrupt discontinuation (withdrawal syndrome)

Prevention

  • TLS awareness/hydration at initiation in high-burden disease
  • Renal dose adjustment per label
  • Avoid abrupt cessation; taper when stopping

Renal dose adjustment

Renal dosing is required: the starting dose is reduced in moderate-to-severe renal impairment and in ESKD. In myelofibrosis/PV with platelets 100-150 x10^9/L and moderate-to-severe impairment (CrCl 15-59), and in dialysis-dependent ESKD, the label specifies reduced starting doses; in ESKD on hemodialysis, give a single reduced dose after dialysis on dialysis days. Avoid initiating if CrCl <15 mL/min and not on dialysis. Always titrate to platelets and response.

Dialyzability & ESKD dosing

Ruxolitinib itself is not removed by hemodialysis - dialysate recovery of the parent drug was negligible - but removal of some ACTIVE METABOLITES cannot be ruled out, which matters because ESKD raises the combined parent-plus-active-metabolite exposure about 1.6-fold. Dose AFTER dialysis on hemodialysis days. Highly protein-bound, hepatically (CYP3A4) metabolized small molecule.

Differential diagnosis

Distinguish early tumor-lysis AKI, infection/cytopenia-related prerenal AKI, and withdrawal-syndrome hemodynamic AKI from any unrelated intrinsic renal disease; the drug is rarely the direct nephrotoxic cause.

Monitoring

  • CBC (platelets, neutrophils, hemoglobin) — dose is platelet-driven
  • Creatinine/eGFR to guide dosing; electrolytes and uric acid at initiation in high-burden disease
  • Infection surveillance (including reactivation: HBV, TB, herpes zoster)

Key trials & series

  • COMFORT-I/II — registrational myelofibrosis trials (clinical context)
  • 10-year safety review (Verstovsek, J Hematol Oncol 2023) — cytopenia/infection-dominant profile

Clinical pearls

  • Don't stop ruxolitinib abruptly — withdrawal can precipitate a cytokine-rebound, capillary-leak-like crisis; taper instead.
  • The renal risks are TLS at start and dosing logistics, not a tubulopathy.
  • Ruxolitinib was an independent predictor of transplant-associated TMA in a GVHD cohort, not explained by GVHD severity — a transplant-context signal, not a general ruxolitinib-TMA claim.

Anticancer mechanism

Oral ATP-competitive JAK1/JAK2 inhibitor that dampens dysregulated JAK-STAT signaling (driven by JAK2 V617F and related mutations), reducing splenomegaly, inflammatory cytokines and constitutional symptoms. Approved for intermediate/high-risk myelofibrosis, polycythemia vera, and acute/chronic graft-versus-host disease.

Note

Clinician-flagged as an emerging topic. Well-established agent but with no significant direct renal toxicity; the prerenal/TLS framing is conservative and supported by the long-term safety review.

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

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

  1. 1.Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety.Verstovsek S et al. · J Hematol Oncol · 2023 · PMID 37501130
  2. 2.Acute Kidney Injury in Patients With Cancer: A Review of Onconephrology.Gudsoorkar P et al. · Adv Chronic Kidney Dis · 2021 · PMID 35190106
  3. 3.Tumor Lysis Syndrome.Barbar T et al. · Adv Chronic Kidney Dis · 2021 · PMID 35190110
  4. 4.New drug toxicities in the onco-nephrology world.Perazella MA et al. · Kidney Int · 2015 · PMID 25671763
  5. 5.Predictors of Transplant-Associated Thrombotic Microangiopathy in Patients With Overlap or Chronic Graft-vs-Host-Disease.Gavriilaki E et al. · Transplant Proc · 2021 · PMID 34417030

Case reports & series (2)

The weakest rung of clinical evidence — single-patient and small-series reports, strongest first. Each carries a heuristic strength grade (A Strong / B Moderate / C Limited) inferred from its abstract and journal, not a formal appraisal. Weigh well below the primary references above.

  1. C1.[C · Limited]Ruxolitinib-associated Karyomegalic Interstitial Nephritis Without FAN1 Mutation: Expanding the Etiology to JAK Inhibitors.Aldana S et al. · Nephron · 2026 · PMID 42139177
  2. C2.[C · Limited]Severe Hypocalcemia During JAK1/2 Inhibitor Therapy for Myelofibrosis in a Patient with Liver Cirrhosis.Kurumazaki M et al. · Intern Med · 2025 · PMID 39814384
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.