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Nitrosourea alkylator

Streptozocin

Zanosar · STZ

Nitrosourea alkylator · approved 1982 · 8 references

A glucose-mimicking nitrosourea that the proximal tubule eagerly takes up and pays for with Fanconi syndrome.

Signature injury
Fanconi Syndrome
Severity
Severe
Reversibility
Partially reversible
Onset
Within weeks of therapy; worsens with cumulative dose; abrupt AKI possible on re-challenge.

Signature kidney injury & incidence

Fanconi Syndrome — representative incidence ~30%.

Nephrotoxicity is the major dose-limiting toxicity; transient proteinuria, tubular dysfunction and azotemia are common and a sizable minority develop clinically significant renal impairment, though precise rates are not uniformly quantified. Reported rate: decrease in estimated glomerular filtration rate of at least 25% during treatment in 30% — 111 patients (27 prospective + 84 retrospective) with locally advanced or metastatic well-differentiated digestive… (Legoux 2021, PMID 33751987).

Source: Legoux et al., Clin Res Hepatol Gastroenterol 2021

Reported injury signatures: Fanconi Syndrome, Acute Tubular Necrosis, Electrolyte Disturbance.

Renal toxicity profile

  1. Fanconi SyndromePrimary
  2. Acute Tubular NecrosisSecondary
  3. Electrolyte DisturbanceSecondary

Onset timing & rechallenge

Subacute (~1–6 weeks) — Tubular injury within weeks, worsening with cumulative dose.

Rechallenge: High recurrence risk — Abrupt AKI can recur on re-challenge.

Mechanism of kidney injury

GLUT2-mediated uptake concentrates the drug in S1-S3 proximal tubular cells, where alkylation and NAD+ depletion produce tubular cell injury and a proximal (type II) renal tubular acidosis / Fanconi picture - urinary wasting of phosphate, potassium, bicarbonate, glucose and amino acids. Defective tubular acidification is demonstrable functionally. Progressive tubular necrosis, squamous metaplasia and tubulointerstitial damage with azotemia follow cumulative dosing.

Clinical presentation

Proteinuria is typically the earliest sign, followed by glycosuria with normal blood glucose, aminoaciduria, hypophosphatemia, hypokalemia, hypouricemia, type II RTA, and rising creatinine. Abrupt AKI can follow a single additional dose after a previously tolerated course.

Management

Discontinue or reduce dose at the first sign of tubular proteinuria or falling GFR; supportive correction of electrolytes, phosphate and acidosis. Early injury may stabilize, but advanced damage can be irreversible and progress to chronic kidney disease.

Risk factors

  • High cumulative dose
  • Pre-existing renal impairment
  • Volume depletion
  • Concurrent nephrotoxins
  • Re-challenge after a treatment interval

Prevention

  • Hold the dose for significant proteinuria
  • Dose reduction for renal dysfunction; consider divided/lower scheduling

Renal dose adjustment

Reduce dose and lengthen interval for impaired renal function; hold for new or worsening proteinuria or rising creatinine. Modern reviews emphasize scheduling (lower per-dose, fractionated) to cap cumulative tubular exposure in pNET.

Dialyzability & ESKD dosing

Small, renally cleared molecule; specific HD removal data are limited and it is rarely used in ESKD. Avoid in significant renal impairment rather than relying on dialytic clearance.

Differential diagnosis

Fanconi physiology (glycosuria with normal glucose, hypophosphatemia, hypouricemia, type II RTA, low-molecular-weight proteinuria) distinguishes streptozocin tubulopathy from glomerular proteinuria and from prerenal azotemia. The combination of euglycemic glycosuria plus phosphaturia is the fingerprint.

Monitoring

  • Quantitative urine protein before every dose
  • Serum creatinine, phosphate, potassium, bicarbonate each cycle
  • Urine glucose / serum glucose discordance (glycosuria with euglycemia)

Key trials & series

  • Hall-Craggs Hum Pathol 1982 - classic clinical AKI-on-re-challenge case with tubular pathology
  • Fennell & Falls Clin Nephrol 1981 - functional proof of the tubular acidification defect
  • Fazio Cancer Treat Rev 2026 - modern pNET scheduling to minimize nephrotoxicity

Clinical pearls

  • Check a urine protein BEFORE each dose - rising proteinuria is the earliest, most actionable warning.
  • A single re-challenge dose after a stable course can trigger abrupt acute renal failure; do not assume prior tolerance protects the kidney.
  • The same GLUT2 uptake that makes it islet-selective makes the proximal tubule the target organ.

Anticancer mechanism

Glucosamine-nitrosourea that alkylates DNA (and depletes NAD+ via PARP activation) and is preferentially taken up by GLUT2-expressing cells, the basis of both its islet-cell selectivity and its proximal tubular toxicity. Used for metastatic islet cell (pancreatic neuroendocrine) tumors and malignant carcinoid.

Note

Proteinuria monitoring before each cycle is the classic safeguard; the proximal tubular/Fanconi signature is well described in onconephrology reviews and pathology series.

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) — 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

References

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

  1. 1.Renal function in patients receiving streptozocin for locally advanced or metastatic digestive neuroendocrine tumours: results of the Streptotox-FFCD 0906 studyLegoux JL et al. · Clin Res Hepatol Gastroenterol · 2021 · PMID 33751987
  2. 2.Acute renal failure and renal tubular squamous metaplasia following treatment with streptozotocin.Hall-Craggs M et al. · Hum Pathol · 1982 · PMID 6281169
  3. 3.Streptozotocin nephrotoxicity: studies on the defect in renal tubular acidification.Fennell JS et al. · Clin Nephrol · 1981 · PMID 6260405
  4. 4.Streptozotocin revisited: Pharmacological determinants supporting new scheduling strategies in neuroendocrine tumours.Fazio N et al. · Cancer Treat Rev · 2026 · PMID 42061024
  5. 5.Comparative nephrotoxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) and chlorozotocin: functional-structural correlations in the Fischer 344 rat.Kramer RA et al. · Toxicol Appl Pharmacol · 1986 · PMID 2937179
  6. 6.Sequential morphologic analysis of the nephrotoxicity produced in rats by single doses of chlorozotocin.Dees JH et al. · Toxicol Pathol · 1986 · PMID 2945250
  7. 7.Anticancer drug-induced kidney disorders.Kintzel PE · Drug Saf · 2001 · PMID 11219485
  8. 8.Nephrotoxicity of semustine.Weiss RB et al. · Cancer Treat Rep · 1983 · PMID 6360348

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]Indomethacin in streptozocin-induced nephrogenic diabetes insipidus.Delaney V et al. · Am J Kidney Dis · 1987 · PMID 2949606
  2. C2.[C · Limited]Uric acid nephrolithiasis and acute renal failure secondary to streptozotocin nephrotoxicity.Hricik DE et al. · Am J Med · 1988 · PMID 2827466
Educational monograph from NephTox (nephtox.com). Not medical advice — verify against current guidelines before any clinical decision.