What is the most likely cause of acute kidney injury in a patient receiving carfilzomib (Kyprolis) who also has diarrhea, and how should it be managed?

Acute Kidney Injury in a Patient Receiving Carfilzomib with Diarrhea

The most likely cause of AKI in this patient is volume depletion from diarrhea-induced hypovolemia, though carfilzomib-induced direct nephrotoxicity (including thrombotic microangiopathy) must be urgently evaluated and excluded. 1, 2

Immediate Diagnostic Approach

Volume Status Assessment

• Assess for hypovolemic AKI first by examining for signs of volume depletion: orthostatic hypotension, decreased skin turgor, dry mucous membranes, and reduced urine output 3
• Check fractional excretion of sodium (FENa): **FENa <1% suggests prerenal causes including volume depletion**, while FENa >1% suggests intrinsic renal injury such as acute tubular necrosis or drug-induced injury 3
• Obtain urinalysis immediately to assess for hematuria, proteinuria, or abnormal sediment that would indicate structural kidney disease 3

Carfilzomib-Specific Toxicity Evaluation

• Monitor for thrombotic microangiopathy (TMA), which occurs in patients receiving carfilzomib and presents with the triad of hemolytic anemia (median hemoglobin 8.3 g/dL), thrombocytopenia (median platelet count 18 × 10⁹/L), and AKI 2
• Check complete blood count, peripheral blood smear for schistocytes, LDH (median 1192 IU/L in carfilzomib-TMA), haptoglobin, and direct Coombs test 2
• The median time to TMA onset is 42 days from carfilzomib initiation (range 1-1825 days), with median of 3 cycles 2
• Note that ADAMTS13 activity is typically normal in carfilzomib-induced TMA (62.1% of cases), distinguishing it from thrombotic thrombocytopenic purpura 2

Management Algorithm

Step 1: Immediate Interventions

• Discontinue carfilzomib immediately if TMA is suspected, as this is the cornerstone of management 1, 2
• Administer albumin at 1 g/kg body weight (maximum 100 g/day) as a fluid challenge to assess volume responsiveness 3
• In hypovolemic AKI, volume replacement should reduce serum creatinine by ≥0.3 mg/dL from baseline 3
• Adjust or discontinue any concurrent diuretics and reduce lactulose dosing to minimize diarrhea 3

Step 2: If Volume Repletion Fails

• If serum creatinine does not improve with fluid challenge, suspect carfilzomib-induced nephrotoxicity 3, 1
• The FDA label warns that acute renal failure occurs in approximately 9% of patients receiving carfilzomib, with higher risk in those with baseline reduced creatinine clearance 1
• Monitor renal function with regular serum creatinine and estimated creatinine clearance measurements 1

Step 3: TMA-Specific Treatment

• If TMA is confirmed, initiate therapeutic plasma exchange (TPE) immediately while awaiting further diagnostic workup 4, 2
• Consider eculizumab (complement inhibitor) if TPE alone is insufficient, as it has shown impressive improvement in kidney function and blood values in carfilzomib-induced TMA 4, 2
• Treatment duration with eculizumab is typically 2 months, with good response rates and no recurrence reported 4
• Hemodialysis may be necessary in 39.4% of cases with severe AKI 2

Critical Pitfalls to Avoid

Do Not Overlook Dual Pathology

• Patients can have both volume depletion AND carfilzomib nephrotoxicity simultaneously 5, 1
• The presence of diarrhea does not exclude drug-induced kidney injury, as carfilzomib carries independent nephrotoxic risk 1, 6

Do Not Delay Carfilzomib Discontinuation

• Carfilzomib should be withheld for Grade 3 or 4 renal adverse reactions until recovery, with consideration for dose reduction upon restart only after careful benefit-risk assessment 1
• The FDA label specifically states to reduce or withhold dose as appropriate when renal dysfunction occurs 1

Monitor for Additional Carfilzomib Toxicities

• Assess for concurrent cardiac toxicity (heart failure, decreased ejection fraction), as carfilzomib causes cardiac events in 8% of patients 1
• Check blood pressure regularly, as hypertension occurs in 17-34% of patients on carfilzomib-containing regimens 1
• Ensure adequate hydration is balanced against volume overload risk, especially in patients with cardiac dysfunction 1

Prognosis and Follow-Up

• Clinical response rates after carfilzomib discontinuation and appropriate treatment reach 86.4% (57 of 66 patients in the largest case series) 2
• Partial resolution of proteinuria and hypertension typically occurs within 8 weeks of carfilzomib discontinuation in TMA cases 7
• Long-term monitoring is essential, as some patients develop persistent donor-specific antibodies or chronic kidney changes despite initial improvement 8