Cyclophosphamide

SIADH / Hyponatremia — representative incidence ~52%.

Dose-related hyponatremia (not reliably quantified); hemorrhagic cystitis ~5–20%, lower with mesna prophylaxis. Reported rate: hyponatremia in 52% — 69 adults who received high-dose cyclophosphamide therapy at a single center 2010-2014 (retrospective cohort (Bonella 2017, PMID 29890094).

Source: Bonella et al., Rev Fac Cien Med Univ Nac Cordoba 2017

Reported injury signatures: SIADH / Hyponatremia, Hemorrhagic Cystitis.

1. SIADH / HyponatremiaPrimarySIADH with hyponatremia is a recognized complication of high-dose cyclophosphamide (direct collecting-duct water retention); described at case/mechanistic level with no cohort incidence denominator.
2. Hemorrhagic CystitisSecondary~2.7%Hemorrhagic cystitis in 22/805 (2.7%) cyclophosphamide-treated systemic necrotizing vasculitis patients over 4,230 patient-years; risk driven by cumulative dose and oral (vs IV) administration. Higher and dose-limiting in high-dose/conditioning settings without mesna.

Hyperacute (<24 h) — Hyponatremia within hours of dosing; cystitis is acute.

• High-dose IV regimens
• Concurrent hypotonic fluids

• Use isotonic rather than hypotonic fluids
• Mesna + hydration for cystitis

• Serum sodium at baseline and within 24-48 h after high-dose IV cyclophosphamide, watching for acute dilutional hyponatremia/SIADH, especially when large hypotonic fluid volumes are co-administered for cystitis prophylaxis
• Strict intake/output and daily weights during and after high-dose infusions to detect water retention before symptomatic hyponatremia develops
• Urinalysis/urine dipstick for hematuria during and after therapy as an early sign of acrolein-mediated hemorrhagic cystitis
• Serum creatinine/electrolytes and, in high tumor-burden hematologic disease, tumor lysis labs (K, phosphate, uric acid) around initial dosing
• Symptom review for headache, nausea, confusion or seizures that may signal acute hyponatremia

• CYCLOPS (Ann Rheum Dis/JAMA 2009, de Groot) — pulse vs daily oral cyclophosphamide in ANCA vasculitis; lower cumulative dose with pulse dosing, relevant to cumulative-exposure toxicity including bladder
• Euro-Lupus Nephritis Trial (Houssiau, Arthritis Rheum 2002) — low-dose vs high-dose IV cyclophosphamide in lupus nephritis showed equivalent renal efficacy with reduced cumulative exposure/toxicity

• The dominant 'renal' signature is acute, dose-dependent hyponatremia/SIADH after high-dose IV cyclophosphamide — give isotonic rather than hypotonic fluids and avoid overhydration with free water to prevent symptomatic, occasionally seizure-inducing, water intoxication.
• Hemorrhagic cystitis is caused by the metabolite acrolein concentrating in urine, not by parenchymal kidney injury; prevent it with mesna (which detoxifies acrolein in the bladder) plus aggressive hydration and frequent voiding.
• Unlike its analog ifosfamide, cyclophosphamide rarely causes proximal tubular dysfunction or Fanconi syndrome — overt parenchymal nephrotoxicity is uncommon and the agent is generally regarded as mild for the kidney at standard doses.
• The hyponatremia is usually self-limited as the drug clears; management is fluid restriction and isotonic-fluid correction rather than chronic SIADH therapy, with attention to avoiding overly rapid sodium correction.
• Cumulative dose drives long-term urologic risk (chronic cystitis, fibrosis, and bladder malignancy), so dose-sparing regimens (e.g., pulse IV or Euro-Lupus low-dose protocols) reduce toxicity without sacrificing efficacy in autoimmune indications.

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) — Conventional cytotoxic chemotherapy-associated nephrotoxicity: consensus report of the 34th Acute Disease Quality Initiative (ADQI) WorkgroupCisplatin is identified as a leading cytotoxic nephrotoxin; the workgroup details preventive measures (adequate isotonic hydration, correction of volume depletion, avoidance of concurrent nephrotoxins, attention to electrolyte/magnesium wasting) and management of cisplatin-associated AKI, with a research agenda for knowledge gaps.Kidney Int · PMID 41881107
• 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