| 6. Kidney toxicities |
Nephritis and kidney dysfunction – diagnosis and monitoring: - Clinical presentation and diagnosis.
- Definite ICPi-related nephritis or AKI:
- Kidney biopsy-confirmed diagnosis compatible with ICPi nephritis or AKI, and after clinical review of risk factors.¶
- Probable ICPi-related nephritis or acute kidney failure:
- Both of the following:
- Sustained increase in serum creatinine ≥50% on at least two consecutive values or need for RRT, after clinical review of risk factors.¶
- Absence of an alternative plausible etiology.
- And at least one of the following:
- Sterile pyuria (≥5 WBCs/hpf).
- Concomitant or recent extrarenal irAE-eosinophilia (≥500 cells per microliter).
- Possible ICPi-related nephritis or acute kidney failure:
- Both of the following:
- Increase in serum creatinine ≥50%.
- Need for RRT nephritis or AKI is not readily attributable to alternative causes.
Monitoring: - Monitor patients for elevated serum creatinine before every dose.
- Routine urinalysis is not necessary, other than to rule out UTIs etc.
- For any suspected immune-mediated adverse reactions, exclude other causes (refer to below).
- For suspected kidney irAE obtain urinalysis, consider referral to nephrology.
- For patients receiving combination therapy with ICPis and other agents, assess the potential contribution of the non-iCPI treatment to the kidney failure.
- Assess for concomitant medications, prescribed and OTC, herbals, vitamins, nephrotoxic agents, or contrast media.
- If no potential alternative cause of AKI is identified, then one can assume it is ICPi-related and should forego biopsy.
- Swift treatment of autoimmune component is important.
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| 6.1. Nephritis or AKI |
| Grading | Management |
| G1: Creatinine level increase of >0.3 mg/dL; creatinine 1.5 to 2.0 times above baseline. | - Consider temporarily holding ICPi and/or other potential contributing agents in combination regimens, pending consideration of potential alternative etiologies (recent IV contrast, medications, fluid status, and UTI) and baseline kidney function. A change that is still <1.5 ULN could be meaningful.
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| G2: Creatinine 2 to 3 times above baseline. | - Hold ICPi temporarily.
- Consult nephrology.
- Evaluate for other causes (recent IV contrast, medications, and fluid status). If other etiologies are ruled out, administer 0.5 to 1 mg/kg/day prednisone equivalents.
- If worsening or no improvement after 1 week, increase to 1 to 2 mg/kg/day prednisone equivalents and permanently discontinue ICPi.
- If improved to ≤G1, taper steroids over at least 4 weeks.
- If no recurrence of CRI discuss resumption of ICPi with patient after taking into account the risks and benefits. Resumption of ICPi can be considered once steroids have been successfully tapered to ≤10 mg/day or discontinued.
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G3: Creatinine >3 times baseline or >4.0 mg/dL; hospitalization indicated.
G4: Life-threatening consequences; dialysis indicated; creatinine 6 times above baseline. | - Permanently discontinue ICPi if ICPi is directly implicated in kidney toxicity.
- Consult nephrology.
- Evaluate for other causes (recent IV contrast, medications, fluid status, and UTI).
- Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent).
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Additional considerations: - Monitor creatinine weekly.
- Reflex kidney biopsy should be discouraged until steroid treatment has been attempted.
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| 6.2. Nephritis or AKI – follow-up |
| Grading | Management |
| G1: Creatinine level increase of >0.3 mg/dL; creatinine 1.5 to 2.0 times above baseline. | - If improved to baseline:
- Resume routine creatinine monitoring.
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| G2: Creatinine 2 to 3 times above baseline. | - If improved to grade 1:
- Taper corticosteroids over at least 4 weeks before resuming treatment with routine creatinine monitoring.
- If elevations persist >7 days or worsen and no other cause found, treat as grade 3.
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| G3: Creatinine >3 times baseline or >4.0 mg/dL; hospitalization indicated. | - If improved to grade 1:
- Taper corticosteroids over at least 4 weeks.
- If elevations persist >3 to 5 days or worsen, consider additional immunosuppression (eg, infliximab, azathioprine, cyclophosphamide [monthly], cyclosporine, and mycophenolate).
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| G4: Life-threatening consequences; dialysis indicated; creatinine 6 times above baseline. | - If improved to grade 1:
- Taper corticosteroids over at least 4 weeks.
- If elevations persist >2 to 3 days or worsen, consider additional immunosuppression (eg, infliximab, azathioprine, cyclophosphamide [monthly], cyclosporine, and mycophenolate).
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