Learning objectives
The reader should be able to classify AKI in cancer patients, identify therapy-specific nephrotoxicity, recognize tumor lysis and hypercalcemia emergencies, evaluate immune checkpoint inhibitor-associated AKI, diagnose paraneoplastic and monoclonal kidney disease, adjust cancer therapy safely in CKD, and coordinate nephrology–oncology decisions about biopsy, rechallenge, and kidney replacement therapy.
Guideline currency. This chapter incorporates the 2025 ADQI consensus on anticancer-therapy nephrotoxicity and the 2025 expert position statement on immune checkpoint inhibitor-associated AKI. Current practice requires mechanism-based diagnosis and shared decision-making rather than assuming every creatinine rise is drug toxicity.1
21.1 A mechanism-and-timing framework
Kidney injury in cancer may result from volume depletion, sepsis, obstruction, tumor infiltration, hypercalcemia, tumor lysis, monoclonal proteins, paraneoplastic glomerular disease, chemotherapy, targeted therapy, immunotherapy, radiation, or unrelated kidney disease. Construct a timeline of cancer type and burden, treatment exposure, dose and schedule, contrast, infection, blood pressure, urinalysis, and previous kidney function.
The first triage questions are: Is there shock or sepsis? Is there obstruction? Is there tumor lysis or hypercalcemia? Is there a glomerular or TMA phenotype? Is there a therapy that should be held immediately? Does the diagnosis require biopsy before steroids or cancer-therapy rechallenge?
21.2 Therapy-associated kidney injury
Cisplatin causes dose-dependent proximal tubular injury, magnesium wasting, salt wasting, and AKI. Prevention includes risk assessment, appropriate hydration, avoidance of concurrent nephrotoxins, electrolyte monitoring, and oncology-directed dose or schedule modification. Methotrexate can cause delayed clearance and crystal nephropathy; high-dose regimens require protocolized hydration, urine alkalinization, leucovorin rescue, serial drug levels, and escalation to glucarpidase in selected delayed-clearance emergencies. Ifosfamide can cause proximal tubulopathy/Fanconi syndrome and hemorrhagic cystitis; mesna protects against acrolein-mediated bladder injury but does not prevent Fanconi syndrome.
Gemcitabine and some other agents can cause TMA, presenting with hypertension, AKI, thrombocytopenia, hemolysis, and proteinuria. VEGF pathway inhibitors may cause hypertension, albuminuria, TMA, and glomerular lesions. EGFR and other targeted agents may cause electrolyte abnormalities or interstitial injury. Bisphosphonates and denosumab require kidney-function and calcium assessment; dosing and agent selection differ in CKD.
Immune checkpoint inhibitors can cause AKI, most often acute interstitial nephritis, but also glomerular disease, TMA, vasculitis, and electrolyte disorders. Proton-pump inhibitors, NSAIDs, antibiotics, and other co-medications may be the true trigger or a cofactor.
Iodinated contrast should not be described as universally nephrotoxic. Risk assessment should consider baseline eGFR, hemodynamic status, procedure urgency, contrast volume, and alternative causes of AKI. Necessary contrast studies should not be withheld automatically when diagnostic benefit is high.
21.3 Immune checkpoint inhibitor-associated AKI
When ICI-AKI is suspected, repeat creatinine, review all medications, assess volume and hemodynamics, urinalysis and sediment, urine protein, infection, obstruction, contrast, and other nephrotoxins. Check for extrarenal immune-related adverse events. Biopsy is considered when the diagnosis is uncertain, proteinuria is substantial, sediment is active, renal recovery is not occurring, a glomerular lesion is possible, or the result will determine high-stakes immunosuppression or rechallenge.
The ICI is usually held for clinically significant AKI while alternative causes are assessed. Corticosteroid treatment is used for suspected immune-mediated kidney injury after exclusion of infection and other causes, with dose and taper guided by severity and response. Rechallenge is a multidisciplinary decision incorporating cancer prognosis, AKI severity, biopsy information, recovery, alternative agents, and patient preference. Relapse risk is real but not uniform.
21.4 Tumor lysis syndrome
TLS is an oncologic emergency characterized by hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia, AKI, arrhythmia, seizures, and sometimes sudden death. Risk depends on tumor burden, proliferation rate, chemosensitivity, baseline uric acid, LDH, kidney function, hydration, and treatment modality. Prevention requires risk stratification, hydration when appropriate, frequent laboratory monitoring, and urate-lowering therapy. Allopurinol prevents new uric acid formation but does not rapidly remove existing urate. Rasburicase is preferred in many high-risk settings or established hyperuricemia when not contraindicated by G6PD deficiency. Avoid routine combination therapy unless a protocol specifically supports it.
Treat hyperkalemia, phosphate and calcium disturbances, acidosis, and volume overload promptly. Dialysis is considered for refractory hyperkalemia, severe hyperphosphatemia, symptomatic hypocalcemia due to phosphate, severe acidosis, uremia, or fluid overload.
21.5 Hypercalcemia and obstruction
Malignancy-associated hypercalcemia causes vasoconstriction, nephrogenic diabetes insipidus, volume depletion, AKI, and nephrocalcinosis. Treatment includes isotonic fluid replacement when appropriate, antiresorptive therapy selected according to kidney function, calcitonin for rapid but transient effect, and treatment of the malignancy. Loop diuretics are not routine substitutes for volume resuscitation.
Malignant ureteral obstruction requires rapid imaging and urologic or interventional radiology consultation. Decompression with stent or nephrostomy may preserve kidney function and enable cancer treatment. Post-obstructive diuresis requires careful fluid and electrolyte replacement.
21.6 Paraneoplastic and monoclonal kidney disease
Membranous nephropathy, minimal change disease, FSGS, immune-complex GN, TMA, and amyloidosis may accompany malignancy. A new glomerular syndrome warrants age- and risk-appropriate cancer evaluation, but immunosuppression should not begin without considering infection and active cancer. Monoclonal gammopathy may produce cast nephropathy, AL amyloidosis, light-chain deposition disease, cryoglobulinemic GN, or other MGRS lesions. Biopsy with appropriate typing and rapid hematology referral are central.
21.7 Biopsy, dose adjustment, and kidney replacement therapy
Kidney biopsy should be considered when the diagnosis is uncertain, the urine phenotype is glomerular, the injury is not improving, or the result will alter cancer therapy, immunosuppression, or prognosis. In thrombocytopenia or anticoagulation, bleeding risk must be corrected or an alternative approach considered.
Cancer drug dosing should use a validated kidney-function method appropriate to the drug, avoid uncritical substitution of eGFR for measured clearance, and account for dialysis clearance and extracorporeal therapies. Kidney replacement therapy should be offered using standard indications while incorporating prognosis, treatment intent, reversibility, patient goals, and expected access to cancer therapy.
Clinical pearls
- Build a timeline before labeling AKI as cancer-drug toxicity.
- ICI-AKI is a diagnosis of exclusion; PPIs, NSAIDs, antibiotics, obstruction, infection, and contrast may be alternatives or cofactors.
- Biopsy is particularly valuable when proteinuria, active sediment, or uncertainty suggests a lesion other than AIN.
- Mesna prevents ifosfamide cystitis, not Fanconi syndrome.
- Allopurinol prevents new uric acid formation; rasburicase rapidly degrades existing urate.
- Check G6PD status before rasburicase when feasible.
- VEGF inhibition can cause hypertension, proteinuria, and TMA.
- Malignant obstruction is a reversible cause of kidney dysfunction and should be decompressed urgently.
- Necessary iodinated contrast is not automatically contraindicated in CKD.
- Dialysis decisions should include cancer treatment intent and patient goals, not creatinine alone.
| Mechanism | Typical clues | First response |
|---|---|---|
| Cisplatin tubular injury | AKI, magnesium wasting, salt wasting | Hydration, avoid nephrotoxins, monitor and adjust regimen |
| ICI-associated AKI | AKI with pyuria or variable sediment | Exclude alternatives, review co-medications, coordinate holding/rechallenge |
| Tumor lysis syndrome | Hyperkalemia, hyperphosphatemia, hypocalcemia, hyperuricemia | Risk-stratified hydration, allopurinol/rasburicase, intensive monitoring |
| VEGF-associated TMA | Hypertension, proteinuria, thrombocytopenia, hemolysis | Hold/adjust therapy and evaluate TMA urgently |
Summary
Onco-nephrology requires mechanism-based reasoning across cancer, therapy, and kidney disease. The essential emergencies are TLS, hypercalcemia, obstruction, severe drug toxicity, TMA, sepsis, and rapidly progressive glomerular disease. ICI-AKI requires systematic exclusion of competing causes and coordinated decisions about steroids, biopsy, and rechallenge. Prevention, early recognition, dose adjustment, and collaboration with oncology can preserve both kidney function and access to effective cancer therapy.
Question 1
A patient receiving pembrolizumab develops creatinine doubling and mild pyuria while taking a PPI and NSAID. What is the best initial approach?
A. Assume ICI-AIN and give steroids without evaluation. B. Review and stop potential nephrotoxins when feasible, assess infection/obstruction/volume, and coordinate ICI management. C. Continue all medicines and wait 3 months. D. Start dialysis immediately.
Answer: B. ICI-AKI is a diagnosis of exclusion and co-medications are frequent contributors.
Question 2
Which treatment best prevents new uric acid formation in TLS?
A. Rasburicase only B. Allopurinol C. Loop diuretic only D. Calcium gluconate
Answer: B. Allopurinol inhibits xanthine oxidase; rasburicase degrades existing urate rapidly.
Question 3
A patient with high-risk TLS has hyperuricemia and G6PD deficiency. Which strategy is most appropriate?
A. Give rasburicase without concern. B. Use a specialist-directed alternative such as allopurinol with intensive monitoring and metabolic control. C. Avoid hydration. D. Give calcium immediately for asymptomatic hypocalcemia.
Answer: B. Rasburicase is contraindicated or unsafe in G6PD deficiency; management requires protocolized specialist care.
Question 4
Which finding most suggests VEGF-inhibitor-associated TMA?
A. Isolated mild hypomagnesemia B. New hypertension, proteinuria, thrombocytopenia, hemolysis, and AKI C. Polyuria after obstruction relief D. Low uric acid
Answer: B. This is a TMA-compatible phenotype.
Question 5
What is the role of kidney biopsy in suspected ICI-AKI?
A. It is required in every patient. B. It is never useful. C. It is considered when uncertainty, significant proteinuria, active sediment, atypical course, or treatment/rechallenge consequences make histology valuable. D. It is contraindicated during cancer therapy.
Answer: C. Biopsy is individualized and can prevent inappropriate treatment.
Question 6
Which statement about iodinated contrast is most accurate?
A. It is universally nephrotoxic. B. It should never be used in CKD. C. Risk is context-dependent; necessary studies should be performed with appropriate assessment and mitigation. D. It causes TLS.
Answer: C. Contrast-associated AKI risk must be assessed in context.