Acute renal failure is a typical serious side-effect of intravenous polyvalent immunoglobulins. Patients with ARF attributed to IVIGs typically had high-dose therapy with sucrose-stabilised formulations
Department of Public Health
Grenoble University Hospital
Intravenous polyvalent immunoglobulins (IVIGs), which are blood-derived products, are generally well tolerated. However, common less severe side-effects include headaches, urticaria, low-grade fever, myalgia and nausea. Because of IVIGs’ therapeutic use in various autoimmune and chronic inflammatory diseases, serious side-effects have been progressively highlighted. Such adverse effects include aseptic meningitis, stroke, myocardial infarction, thrombotic complications, anaphylaxis and acute renal failure (ARF). ARF is one of the most common serious side-effects – occurring in 6.5% of Levy’s retrospective cohort of 119 patients receiving IVIGs. In 1998, the FDA’s Center for Biologics Evaluation and Research received more than 114 worldwide adverse-event reports of renal dysfunction and/or acute renal failure associated with IVIGs since their first use in 1981. ARF secondary to IVIGs is more likely to occur with sucrose-stabilised formulations.[1,3-6] ARF is often reversible but many patients require haemodialysis. Forty per cent of 88 American case-patients reported to the FDA required dialysis, and 15% died. Patients with ARF attributed to IVIGs generally received high-dose therapy (0.8-5â€‰g/kg/cycle). The French Pharmacovigilance Commission identified different risk factors for developing ARF with IVIGs, such as pre-existing renal failure, diabetes, obesity, hypovolaemia and age over 65. Patients considered to be at high risk are also those with inadequate hydration, sepsis, paraproteinaemia or with an associated concomitant nephrotoxic drug.[1,3] We describe an essentially normal male who developed low-dose sucrose-based IVIGs-induced ARF after three years of uneventful treatment with this medication.
A 69-year-old male was diagnosed in 2002 with inclusion body myositis associated with Gougerot-SjÃ¶gren’s syndrome. He has a history of gout and depression. He received nine cycles of immunotherapy (0.4â€‰g/kg bodyweight of IVIGs a day, for five days per cycle) between March 2003 and November 2004 without significant complications. TÃ©gÃ©lineÂ® (Laboratoire FranÃ§ais de Fractionnement et des Biotechnologies), containing sucrose, was the IVIG commonly provided by the pharmacy. When TÃ©gÃ©line was not available a glucose-containing IVIG, EndobulineÂ® (Baxter), was used. Our patient received TÃ©gÃ©line for six cycles and Endobuline once. Another two cycles with both IVIGs (sucrose- and glucose-containing) were used.
The patient was rehospitalised in January 2006 due to exacerbation of his myositis. On admission, medication included paroxetine 20â€‰mg/day and allopurinol 150â€‰mg/day. He weighed 76â€‰kg. Laboratory results showed 141â€‰mmol/l serum sodium, 4.1â€‰mmol/l serum potassium, 4.4â€‰mmol/l blood glucose, 464â€‰Âµmol/l uricaemia, initial blood urea nitrogen 7.8â€‰mmol/l and serum creatinine 57â€‰Âµmol/l corresponding to 131â€‰ml/min clearance. The patient received 0.4â€‰g/kg bodyweight of IVIGs for five consecutive days. The 30â€‰g daily dose was infused over four hours. On the fifth day of treatment, creatinine and urea nitrogen levels increased and IVIG perfusion immediately stopped; the last 10â€‰g of his dose were not administered. Physical examination on day six revealed a 4â€‰kg bodyweight increase because of generalised oedema. Urine output decreased to 200â€‰ml/day, and uricaemia level increased to 515â€‰Âµmol/l on the seventh day. Creatinine and urea nitrogen levels reached 418â€‰Âµmol/l and 20â€‰mmol/l respectively on day seven. Urine analysis on the eighth day showed 0.82â€‰g/l protein, sodium 7.4â€‰mmol/J. Upon discontinuation of IVIGs, a gradual increase of urine output was observed, and serum creatinine started to decrease on the eighth and returned to baseline on the 12th day. Renal biopsy was not required.
This acute renal failure did not require haemodialysis; the patient was treated by hyperhydration with 10% sodium chloride (40â€‰ml/J), 4.2% sodium bicarbonate (40â€‰ml/J), 10% calcium gluconate (5â€‰ml/J), 2.5% glucose (1â€‰l/J) and 10% intravenous magnesium (5â€‰ml/J) for three days. He also received 1â€‰g furosemide on day seven.
Despite his age, our patient did not show risk factors pertaining to the development of an ARF with IVIG therapy. Specifically, he had no baseline renal insufficiency, diabetes or dehydration. ARF occurred on the fifth day of IVIG administration. These data are similar to those reported by the FDA or for Levy’s cohort: renal failure always occurred fewer than seven days after IVIG administration. Serum creatinine levels increased two days after the discontinuation of IVIG therapy. An increase in serum creatinine levels after withdrawal of the treatment is also described by Shrikala and should not turn down the role of IVIGs. Creatinine level returned to baseline after seven days upon discontinuation, as described by Michail8 and Shrikala.
The risk of developing ARF seems to be related to the IVIG dose. It may be more frequent with high-dose-therapy IVIGs, although some studies found no significant differences in the dose of IVIGs administered.
Our patient received the usual IVIG dose of 0.4â€‰mg/kg/J. Maltose and sucrose are added to many IVIG preparations as stabilisers to prevent aggregation of immunoglobulins involved in minor side-effects. Enzymes responsible for the cleavage of sucrose into glucose and fructose are not present in human blood. Because renal cells do not have disaccharidases, sucrose cannot be metabolised and thereby accumulates in the cytoplasm, creating an osmotic gradient across the membrane. Water enters the proximal tubular cells, resulting in swelling and vacuolisation.[3,8] Sucrose may be toxic when it is administered intravenously. It was previously known to provoke an osmotic stress to proximal tubule, leading to a decrease of renal function known as osmotic nephrosis. Stahl and Perazela[10,11] consider sucrose to be the major factor responsible for acute tubular dysfunction induced by IVIGs. Histological features of osmotic nephrosis have been observed in renal biopsies performed on patients with ARF.[8,12] Of ARF cases, 90% have been associated with a sucrose-containing product; the FDA recommends a maximum infusion rate for IVIGs containing sucrose as a stabiliser of 3â€‰mg/kg/min of sucrose. In our case, the daily dose was infused over four hours, corresponding to 3.25â€‰mg/kg/min of sucrose. Our patient’s ARF may be related to the sucrose in the immunoglobulin while renal functions were normal before the treatment and returned to normal after discontinuation. However, there are also case reports of renal failure in patients receiving IVIGs without sucrose, but containing maltose, glycine or glucose as stabiliser.
For the majority of patients, ARF occurred with the first infusion of IVIGs.[1,8] Considering the mechanism of sucrose toxicity, ARF may probably occur at any time. In our case renal biopsy was not performed, but we found no explanation for this ARF other than IVIGs. The slight increase in uricaemia level during this event excluded an ARF caused by allopurinol renal precipitation.
Our patient, who was treated with IVIG therapy for three years, developed reversible ARF. He did not have risk factors except for older age, and he received a low dose of IVIGs. ARF seemed due to a sucrose-containing IVIG preparation.
Healthcare providers should be aware of the risk of ARF associated with IVIGs containing sucrose. Non-sucrose-based products would be a better choice. All IVIG patients should have their renal function monitored closely. â–
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