Gemcitabine

Thrombotic Microangiopathy — representative incidence ~0.015% (0.008–0.078% range across studies).

Estimates span three orders of magnitude by ascertainment. The only figure with a real denominator is the manufacturer safety-database review: 12 cases against 78,800 patient exposures, a crude 0.015% (range 0.008–0.078%). The product characteristics give 0.01%. Against that, a single center reported 2.7% — four of its five cases on nab-paclitaxel/gemcitabine, where a pharmacokinetic interaction is suspected. Historically high mortality: of 23 cases with reported outcome in the literature tally, 11 died within a few weeks, death directly attributed to HUS in two.

Source: Fung et al., Cancer 1999 (PMID 10223245); Allard et al., Eur J Clin Pharmacol 2022 (PMID 35507073); Walter et al., Am J Kidney Dis 2002 (PMID 12324937)

Reported injury signatures: Thrombotic Microangiopathy, Hypertension, Glomerular Injury / Proteinuria, Hemorrhagic Cystitis.

1. Thrombotic MicroangiopathyPrimary~0.31%Cumulative incidence 0.31% in the largest single-institution series (8/2586 patients); older estimates ~0.015% and pooled ranges 0.015-1.4%. Dose-dependent, risk rises as cumulative dose approaches ~20,000 mg/m2.
2. HypertensionSecondaryNew or exacerbated hypertension is a prominent early feature of gemcitabine-associated TMA, seen in 7 of 9 patients and often preceding TMA diagnosis by 0.5-10 weeks.
3. Glomerular Injury / ProteinuriaRareGlomerular endothelial injury underlies the TMA lesion; gemcitabine is listed among conventional chemotherapies causing glomerular disease, but standalone incidence is case-level with no citable rate.
4. Hemorrhagic CystitisRareIntravesical instillation only - chemical/follicular cystitis in NMIBC trials, not a systemic-route toxicity.

Delayed (>6 weeks / cumulative) — TMA emerges after months of cumulative exposure, not from a single dose.

Rechallenge: Contraindicated — Once TMA is suspected the drug is stopped permanently; rechallenge risks recurrence and worse renal outcomes.

• High cumulative dose
• Prior mitomycin
• Hypertension

• No proven pharmacologic prophylaxis

• Check CBC with peripheral smear (schistocytes), LDH, haptoglobin, and creatinine before each cycle — look for the MAHA triad of falling platelets/hemoglobin, rising LDH, and rising creatinine.
• Monitor blood pressure at every visit and have patients self-monitor; new or accelerating/malignant hypertension often precedes the renal/hematologic diagnosis of gemcitabine-TMA by days to weeks.
• Track cumulative gemcitabine dose and treatment duration — risk rises with prolonged exposure (median onset ~8 months, cumulative doses ~9-56 g/m2 in reported series).
• Screen urine for new or worsening proteinuria and hematuria, which reflect the evolving glomerular/vascular injury.
• If TMA labs appear, send ADAMTS13 activity to exclude TTP (gemcitabine-TMA has near-normal ADAMTS13) and stop the drug immediately rather than waiting for biopsy confirmation.

• Humphreys et al. 2004 (Cancer) — largest single-institution series of gemcitabine-associated TMA (incidence ~0.31%, higher than prior 0.015% estimates); new or exacerbated hypertension in 7/9 patients preceded diagnosis and was proposed as an early warning sign.
• Glezerman et al. 2009 (Ann Pharmacother, MSKCC) — cohort analysis linking gemcitabine-associated HUS/TMA to cumulative dose and treatment duration, supporting a dose-dependent toxic mechanism.
• Saif & McGee 2005 (JOP) — case report plus literature review establishing gemcitabine-induced HUS as a distinct, often irreversible entity (biopsy-proven TMA progressing to dialysis despite plasmapheresis and steroids).
• Ritchie et al. 2016 (Cancer Chemother Pharmacol) — retrospective rituximab case series in gemcitabine-HUS reporting durable hematologic and renal recovery when plasma exchange failed, informing complement/immune-directed rescue therapy.

• Hypertension is the clinical tell: new-onset or accelerated/malignant hypertension frequently heralds gemcitabine-TMA and should trigger urgent MAHA labs rather than simply adding an antihypertensive.
• Gemcitabine-TMA is dose/duration-cumulative, not idiosyncratic to a single dose — it typically emerges after many months of therapy, so vigilance must persist throughout treatment, not just at initiation.
• The cornerstone of management is permanent drug discontinuation; dose reduction or rechallenge risks recurrence and worse renal outcomes.
• Plasma exchange is often ineffective (this is not classic TTP); renal recovery is variable and a meaningful subset progress to dialysis-dependent kidney failure or chronic CKD.
• Complement activation is implicated (gemcitabine renal biopsies show prominent capillary complement deposition), providing the rationale for anti-complement therapy (e.g., eculizumab) or rituximab as rescue when TMA persists after drug withdrawal.
• Chemical/follicular cystitis is an intravesical-route gemcitabine toxicity (NMIBC instillation trials); systemic-gemcitabine hemorrhagic cystitis is undocumented, and the urothelial-cancer indication inflates the FAERS term.

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