Cisplatin
Platinol · Platinum agent
Proximal tubular ATN + magnesium wasting; the archetype.
ATNLYTEPRE
SevereOpen →
Hypomethylating agent
Azacitidine
Vidaza · Aza
A hypomethylating agent that, at higher exposures, blunts the proximal tubule into a Fanconi-like acidosis.
ModerateHypomethylating agent · approved 2004
Myelodysplastic syndromesAcute myeloid leukemiaChronic myelomonocytic leukemia
Signature kidney injury
Acute Tubular Necrosis
Proximal tubular dysfunction (proximal/type 2 renal tubular acidosis, polyuria, and glucose/amino-acid/electrolyte wasting) was described with higher-dose azacitidine; with current low-dose subcutaneous/IV regimens overt AKI is uncommon and renal incidence is not well quantified (case-level).
Source: Kintzel, Drug Saf 2001
Toxicity fingerprint
Tap a signature to trace where it strikes the nephron.
Incidence not quantified
SeverityModerate
ReversibilityReversible
Evidence0 refs
Nephron map
Proximal TubuleBulk reabsorption + drug uptake (OCT2, OATs)
Distal Tubule / Collecting DuctFine-tuning of Na, K, Mg, acid & water
Acute Tubular Necrosis
Direct death of tubular epithelial cells — the dose-limiting lesion of the platinums and zoledronate.
Mechanism of kidney injury
Direct proximal tubular epithelial toxicity impairs the apical/basolateral transport machinery (sodium-bicarbonate cotransport, sodium-glucose and sodium-amino-acid cotransport), producing a proximal (type 2) renal tubular acidosis and a Fanconi-like syndrome with bicarbonaturia, glucosuria, aminoaciduria and phosphate/potassium wasting. With heavier exposure, tubular cell injury can progress to acute tubular necrosis. Because azacitidine is incorporated into RNA of metabolically active, mitochondria-rich proximal tubular cells, energy-dependent reabsorption is preferentially disrupted.
Clinical presentation
Non-anion-gap (hyperchloremic) metabolic acidosis with an inappropriately alkaline urine pH for the degree of acidemia, polyuria, normoglycemic glucosuria, hypokalemia and hypophosphatemia; bland urinalysis aside from glucosuria. Creatinine rises in more severe cases.
Onset
During treatment cycles (days to weeks).
Reversibility
Reversible
Anticancer mechanism
Pyrimidine (cytidine) analog incorporated into RNA (the majority) and, after reduction, into DNA. Once in DNA it forms an irreversible covalent adduct with DNA methyltransferase, depleting the enzyme and producing genome-wide hypomethylation that reverses aberrant promoter silencing and restores tumor-suppressor expression. Standard therapy for myelodysplastic syndromes (MDS), acute myeloid leukemia and chronic myelomonocytic leukemia.
Management
Hold or reduce dose for unexplained renal dysfunction or worsening acidosis. The label specifies that if serum bicarbonate falls below 20 mEq/L or creatinine/BUN rise unexplained, the next cycle should be reduced by 50% and resumed only after recovery. Replace bicarbonate, potassium and phosphate; remove concurrent nephrotoxins. Tubular dysfunction typically improves after dose reduction or discontinuation.
Risk factors
- Higher cumulative dose
- Pre-existing chronic kidney disease
- Volume depletion
- Concomitant nephrotoxins
Prevention
- Adequate hydration
- Monitor electrolytes, bicarbonate and creatinine each cycle
- Reduce or delay the next cycle for unexplained renal dysfunction or worsening acidosis
Note · Classic tubular-acidosis signal derives largely from older higher-dose data; modern low-dose renal toxicity is case-level. Importantly, kidney injury in MDS patients is frequently disease- or vasculitis-related rather than drug-induced, which matters for attribution.
Clinical depth
Renal dose adjustment
No starting-dose adjustment is required for baseline renal impairment, but the label mandates a 50% dose reduction of the next cycle if unexplained serum bicarbonate <20 mEq/L or a rise in BUN/creatinine occurs, with resumption only after recovery to baseline. Use with caution and closer monitoring in CKD.
Dialyzability & ESKD dosing
Azacitidine and its metabolites are partly renally cleared; specific hemodialysis removal data are limited. It is given to dialysis patients in practice with careful monitoring, but no validated supplemental dosing exists.
Differential diagnosis
Differentiate drug-induced proximal RTA/Fanconi (normoglycemic glucosuria, hypophosphatemia, low-molecular-weight proteinuria) from MDS-associated kidney disease (often a pauci-immune or ANCA-associated vasculitis with active urine sediment and hematuria) and from prerenal azotemia (bland sediment, FeNa <1%). A kidney biopsy is warranted when MDS-related glomerulonephritis is suspected.
Monitoring
- Serum bicarbonate, BUN and creatinine before each cycle
- Serum potassium and phosphate each cycle
- Urinalysis for glucosuria/proteinuria if tubular dysfunction is suspected
Key trials & series
- AZA-001 survival trial (Lancet Oncol 2009) — established azacitidine in higher-risk MDS (renal effects were uncommon at standard dosing)
- Historical high-dose azacitidine experience underlying the tubular-acidosis signal
Clinical pearls
- Think proximal RTA, not glomerular disease — the hallmark is a normal-anion-gap acidosis with glucosuria despite euglycemia.
- Much of the AKI in azacitidine-treated MDS patients is from the underlying disease (vasculitis), so biopsy before blaming the drug.
- The label gives an explicit bicarbonate threshold (<20 mEq/L) that triggers a 50% dose reduction.
Where it strikes
Nephron segments
Proximal Tubule
Bulk reabsorption + drug uptake (OCT2, OATs)
Injury signatures
Acute Tubular NecrosisFanconi SyndromeElectrolyte Wasting
Evidence
6 peer-reviewed references. Citation metadata via PubMed / NLM.
LandmarkAnticancer drug-induced kidney disorders.Kintzel PE et al. · Drug Saf 2001 · PMID 11219485Describes high-dose azacitidine tubular acidosis with electrolyte, glucose and amino-acid wasting.PMIDKidney involvement in myelodysplastic syndromes.Lafargue MC et al. · Clin Kidney J 2024 · PMID 39099564Multicenter series showing much MDS-associated kidney injury is vasculitic, important for attribution.PMIDAnticancer Drug-Induced Acute Kidney Injury.Izzedine H et al. · Kidney Int Rep 2017 · PMID 29318217Onco-nephrology review of segment-specific drug nephrotoxicity including proximal tubulopathy.PMIDOnconephrology: The intersections between the kidney and cancer.Rosner MH et al. · CA Cancer J Clin 2020 · PMID 32853404Reviews electrolyte disorders and tubulopathies in patients with hematologic malignancies.PMIDKDIGO Controversies Conference on onco-nephrology: kidney disease in hematological malignancies and the burden of cancer after kidney transplantation.Malyszko J et al. · Kidney Int 2020 · PMID 33276867Consensus framing of kidney disease in hematologic malignancies including MDS, aiding attribution of AKI.PMIDNew drug toxicities in the onco-nephrology world.Perazella MA et al. · Kidney Int 2015 · PMID 25671763Onco-nephrology review covering hypomethylating-agent tubular toxicity.