Acute encephalopathy in a kidney transplant recipient following infusion of intravenous immunoglobulin

Dear Sirs, IVIG products differ in their use of stabilizers, pH, osmolality, and their overall risk profiles including neurological, hematological, renal, pulmonary, and dermatological complications (see Table 1). While most adverse effects secondary to IVIG infusion are attributed to the rate of infusion and the large dose of immunoglobulin itself [1], side effects due to stabilizers have also been described [1,2]. Here, we report a kidney transplant recipient with autosomal recessive polycystic kidney disease (ARPKD) and Caroli disease who developed acute encephalopathy following infusion of a glycine-stabilized IVIG product (Gammagard Liquid 10% Baxter Healthcare Corporation, Westlake Village, CA, USA). An 18-year-old male was admitted for the treatment of antibody-mediated rejection (AMR), status 5 years post deceased donor kidney transplant for ARPKD. He had associated hepatic fibrosis with mildly impaired liver function and significant portal hypertension resulting in recurrent ascites and bleeding esophageal varices requiring transjugular intrahepatic portosystemic shunt placement. He also developed recent ascending cholangitis and new onset diabetes after transplant. The donor organ was a 0/6 HLA match with no preformed donor-specific antibodies (DSA) detected. The patient went on to develop multiple episodes of biopsyproven cellular rejection. This admission was precipitated by an acute rise in his serum creatinine to 281 umol/l (baseline 120 umol/l, estimated GFR: 48 ml/min/1.73 m). Renal biopsy demonstrated AMR with diffuse peritubular capillary C4d staining, chronic tubular atrophy, interstitial fibrosis (Banff grade 3), and mild cellular rejection (Banff grade suspicious). Given the patient’s increased infectious risk, he was treated with IVIG following three daily pulses of IV methylprednisolone. The patient received 2 g/kg IVIG (110 g total) given over 8 h at a rate of 1.6 ml/kg/h for the first 300 ml and at 2.8 ml/kg/h for the remaining 800 ml. Shortly prior to the end of the infusion, the patient was noticed to be confused. His vital signs were normal, Glasgow coma score was 12/15, and deep tendon reflexes were mildly increased. The remainder of the physical examination revealed mild peripheral edema and ascites, unchanged from previous examination. Laboratory investigations demonstrated: whole blood sodium 129 mmol/l, plasma sodium 131 mmol/l (139 mmol/l 12 h prior), urea 17.8 mmol/l, creatinine 176 umol/l, and glucose 11.1 mmol/l. Bicarbonate, potassium, calcium, phosphate, magnesium, total protein, serum osmolality, and complete blood count were all normal except for mild thrombocytopenia (stable from previous labs). Serum bilirubin and liver enzymes were normal except gamma-glutamyltransferase was 96 U/l. Albumin and INR were stable at 30 g/l and 1.34, respectively. Tacrolimus trough level drawn the following morning was 5.3 lg/ l. Ammonia and glycine levels were significantly elevated at 84 umol/l (normal: 9–33) and 468 umol/l (normal: 158– 302) when measured 6 h following the infusion. Two hours postinfusion, the patient had become more confused. Given the acute drop in plasma sodium, he was started on a normal saline infusion at 40 ml/h and given 40 mg IV furosemide (0.8 mg/kg). His sodium rose to 135 mmol/l 10 h postinfusion, but there was little clinical improvement. Following a normal CT head, lactulose 20 g twice daily was commenced to treat the hyperammonemia. By evening (20 h postinfusion), his cognition had completely returned to normal and examination was unremarkable. We describe a case of a kidney transplant recipient with ARPKD and Caroli disease who developed acute encephalopathy following a glycine-stabilized IVIG infusion. Hyponatremia, hyperammonemia, and hyperglycinemia were identified, all of which may have contributed to the presentation and each may have been precipitated by the relatively rapid administration of this IVIG product. This case raises concern about the safety of glycine-stabilized IVIG products in patients who have both impaired kidney and liver function. True hyponatremia and pseudohyponatremia following IVIG infusion have each been reported separately in the