Can denosumab (Prolia/Xgeva) cause Acute Kidney Injury (AKI) in a patient with metastatic gallbladder cancer to the liver and pre-existing renal impairment?

Does Denosumab Cause Acute Kidney Injury?

Denosumab does not directly cause acute kidney injury and is specifically preferred over bisphosphonates in patients with pre-existing renal impairment because it requires no dose adjustment for renal function and carries lower renal toxicity risk. 1

Evidence from FDA Drug Label and Guidelines

The FDA drug label explicitly states that "the degree of renal impairment had no effect on the pharmacokinetics of denosumab; thus, dose adjustment for renal impairment is not necessary." 2 This is a critical distinction from bisphosphonates like zoledronic acid, which are renally cleared and can cause acute renal failure. 1

The NCCN Guidelines specifically recommend denosumab as preferred therapy in patients with renal disease because of its favorable renal safety profile compared to bisphosphonates. 1 In a large randomized trial of 1,718 patients with multiple myeloma, denosumab demonstrated lower rates of renal toxicity compared to zoledronic acid. 1

Clinical Context for Your Patient

For a patient with metastatic gallbladder cancer to the liver and pre-existing renal impairment:

• Denosumab can be safely administered without dose adjustment regardless of creatinine clearance, including patients on dialysis 3, 2
• The primary concern is not AKI, but rather hypocalcemia, which occurs in approximately 42% of ESRD patients receiving denosumab compared to 13% in patients with normal renal function 3, 4

Critical Safety Considerations (Not AKI-Related)

Hypocalcemia Prevention is Mandatory

• Correct any pre-existing hypocalcemia before administering denosumab 3, 5
• Provide mandatory calcium supplementation (500-1,000 mg daily) and vitamin D3 (400-800 IU to 1,000-2,000 IU daily) throughout treatment 3, 5
• Monitor serum calcium before each injection, especially after the first few doses 3, 5
• Severe hypocalcemia typically presents 4-35 days after initial or second denosumab treatment and may require hospitalization with IV calcium 5

Monitoring Requirements

• Measure serum calcium, phosphate, vitamin D, PTH, alkaline phosphatase, and creatinine clearance before treatment 3, 5
• Perform mandatory baseline dental examination to reduce osteonecrosis of the jaw risk (1-3% incidence) 3, 5
• Continue calcium monitoring throughout treatment duration 3, 5

Rare Case Report Context

One case report described rhabdomyolysis-induced AKI in a patient receiving simultaneous denosumab and abiraterone therapy (along with chronic statin use). 6 However, this was:

• A single case report with multiple confounding medications
• The causative agent was unclear (could have been abiraterone, statin interaction, or combination)
• This represents an extremely rare event and is not considered a characteristic toxicity of denosumab

Infection Risk in Immunosuppressed Patients

While not AKI-related, one study found increased infection rates in CKD patients on steroids >2.5 mg/day or multiple immunosuppressive medications receiving denosumab (43% developed side effects, with 50% requiring admission for moderate infections). 7 This is relevant for cancer patients but does not represent renal toxicity.

Common Pitfalls to Avoid

• Failure to provide adequate calcium and vitamin D prophylaxis is the most common cause of severe symptomatic hypocalcemia, not inadequate renal monitoring 3
• Do not withhold denosumab due to renal impairment concerns—this is precisely when it should be preferred over bisphosphonates 1, 3
• Do not abruptly discontinue denosumab without follow-up therapy, as this can lead to rebound bone resorption 3