How does Intravenous Immunoglobulin (IVIG) cause Acute Kidney Injury (AKI)?

Mechanism of IVIG-Induced Acute Kidney Injury

IVIG causes AKI primarily through osmotic nephrosis in the proximal tubules, driven by high concentrations of stabilizing agents (particularly sucrose) that create osmotic stress on renal tubular epithelial cells. 1, 2, 3

Primary Pathophysiologic Mechanism

Osmotic Nephrosis

• The dominant mechanism is osmotic injury to proximal tubular epithelial cells caused by stabilizing agents added to IVIG preparations. 2, 3, 4
• Sucrose-containing IVIG products pose the highest risk, with sucrose concentrations reaching 1.67 g sucrose per gram of protein in some formulations. 2
• The large solute load from stabilizers (sucrose, maltose, or glucose) induces acute tubulo-interstitial nephropathy when high doses are administered. 4
• Urine cytology in affected patients demonstrates characteristic osmotic injury to renal tubular epithelial cells. 3

Dose-Dependent Effect

• High-dose IVIG (400-2000 mg/kg) significantly increases AKI risk due to the cumulative osmotic load delivered to the kidneys. 2, 5
• The infusion rate is a critical determinant—faster rates concentrate the osmotic stress over shorter periods. 5, 4

Additional Contributing Mechanisms

Direct Renal Effects

• IVIG carries a black box warning for acute renal failure, indicating FDA recognition of this serious complication. 6, 7
• The FDA label specifically lists nephrotic syndrome as a rare but documented adverse reaction to IVIG administration. 8

Hemodynamic Factors

• Volume overload from the infusion itself can contribute to renal dysfunction, particularly in patients with cardiac disease. 7
• Hyperviscosity from high immunoglobulin concentrations may impair renal microcirculation. 2

High-Risk Patient Populations

Clinicians must identify patients at elevated risk before IVIG administration: 4

• Age >65 years represents an independent risk factor for IVIG-induced AKI. 9, 4
• Pre-existing renal insufficiency (creatinine clearance <60 mL/min) dramatically increases susceptibility. 9, 4
• Diabetes mellitus increases risk through baseline microvascular compromise. 9, 4
• Hypovolemia at the time of infusion concentrates the osmotic load. 4
• Concomitant nephrotoxic medications (NSAIDs, contrast agents, aminoglycosides) compound renal injury. 6, 4

Clinical Presentation and Recovery

• AKI typically manifests with elevated serum creatinine (peak values can reach 8.4 mg/dL from baseline 1.0 mg/dL), often accompanied by nausea, vomiting, fever, and chills. 2
• Anuric renal failure can occur in severe cases. 3
• Recovery of renal function usually occurs within 10 days, though approximately 30% of cases require hemodialysis. 5, 4
• Early dialytic removal of sucrose from circulation can facilitate recovery. 3

Prevention Strategies

The following measures reduce AKI risk in high-risk patients: 4

• Discontinue diuretics before IVIG infusion to avoid volume depletion. 4
• Initiate hydration with normal saline prior to and during infusion. 4
• Avoid concomitant nephrotoxic agents (contrast media, NSAIDs, aminoglycosides). 6, 4
• Use the minimal required dose of IVIG for the clinical indication. 4
• Slow the infusion rate to 1-2 mL/kg/hour rather than standard rates. 2, 4
• Consider glucose-containing IVIG products (0.4 g glucose/g protein) rather than sucrose-containing formulations (1.67 g sucrose/g protein) when high doses are required. 2

Product-Specific Considerations

• While sucrose-containing products (e.g., Sandoglobulin) have been most commonly implicated, AKI has been reported with maltose and glucose-containing preparations as well. 4
• No controlled trials definitively compare AKI rates between different IVIG formulations, but case reports suggest lower risk with glucose-stabilized products. 2, 4
• Clinicians should recognize that AKI may occur with all types of IVIG, regardless of stabilizer. 4

Monitoring Requirements

• Monitor serum creatinine and BUN closely during and after IVIG infusion, particularly in high-risk patients. 7
• Watch for clinical signs of volume overload, especially in cardiac transplant or heart failure patients. 7
• The incidence of IVIG-induced AKI is estimated at <1%, but vigilance is essential given the severity when it occurs. 4