Renal Insufficiency and Failure Associated with Immune Globulin Intravenous Therapy -- United States, 1985-1998
Immune globulin intravenous (IGIV) is a sterile, highly purified immunoglobulin G (IgG) preparation made from pooled human plasma stabilized with glucose, maltose, glycine, sucrose, sorbitol, or albumin and is used as prophylaxis or therapy for various medical disorders. The Food and Drug Administration (FDA) first licensed IGIV in 1981 and has approved its use for six conditions: primary immunodeficiencies, immune-mediated thrombocytopenia, Kawasaki syndrome, recent bone marrow transplantation in patients aged greater than or equal to 20 years, chronic B-cell lymphocytic leukemia, and pediatric human immunodeficiency virus type 1 (HIV-1) infection (Table 1). In clinical practice, IGIV has been known to be used to treat 50-60 unapproved conditions, including acute lymphoblastic leukemia, adult HIV infection, multiple sclerosis, Guillain-Barre syndrome, and chronic inflammatory demyelinating polyneuropathy (1). During June 1985-November 1998, FDA received approximately 120 reports worldwide of renal adverse events (RAEs) (i.e., acute renal failure or insufficiency) following IGIV administration. This report describes the epidemiology of IGIV-associated RAEs in the United States and emphasizes the importance of reviewing indications for IGIV use and implementing precautions during its administration.
In the United States, FDA received 88 reports of cases with clinical and/or laboratory findings consistent with a RAE (i.e., increased serum creatinine, oliguria, and acute renal failure) as determined by the treating health-care provider after IGIV administration. Among the 88 case-patients, the median age was 60.5 years (range: 3-91 years); 48 (55%) were male. Of the 54 case-patients that were reported with conditions associated with acute renal failure, 35 (65%) were aged greater than 65 years, 30 (56%) had diabetes mellitus, and 14 (26%) had prior renal insufficiency; 32 (59%) case-patients had one of these conditions, 19 (35%) had two, and three (6%) had three. Indications for IGIV use were reported in 85 (97%) case-patients and included 39 (46%) hematologic, 20 (23%) immunologic, 17 (20%) neurologic, and nine (11%) infectious diseases. Seventy-nine (90%) case-patients received sucrose-containing IGIV products, seven received IGIV with maltose or glucose, and two received IGIV in which the stabilizer was undetermined.
Of the 33 (38%) case-patients for whom time of RAE onset was available, all occurred less than 7 days following IGIV administration. Baseline serum creatinine levels ranged from 0.3 mg/dL to 5.4 mg/dL (normal: less than 1.5 mg/dL; mean baseline: 1.6 mg/dL). Peak levels (range: 1.4 mg/dL to 14.3 mg/dL; mean peak: 6.2 mg/dL) of serum creatinine were reached on the fifth day (range: 3-8 days). Approximately 35 (40%) patients had severe symptoms requiring dialysis; no significant differences in baseline serum creatinines or other underlying risk factors were found between patients requiring and not requiring dialysis. The mean recovery time of renal function, with or without dialysis, was 10 days (range: 2-38 days) after RAE onset; however, 13 (15%) of the 88 patients died despite therapy. These patients had severe underlying conditions (i.e., cardiac insufficiency, pneumonia, or systemic lupus erythematosis), and the extent to which RAEs contributed to their deaths was undetermined. In seven (47%) for whom data were available, renal histology indicated extensive vacuolization of the proximal tubules, with swelling and narrowing of the tubular lumina consistent with osmotic injury; six of these case-patients received sucrose-containing IGIV preparations. In the remaining eight, the histology findings did not indicate a pattern. In three additional case-patients, vacuolated renal tubular epithelial cells were detected on urinalysis, suggesting possible injury to the kidneys.
Reported by: A Gaines, PhD, F Varricchio, MD, R Kapit, MD, Div of Biostatistics and Epidemiology, Center for Biologics Research and Review, Food and Drug Administration; LR Pierce, MD, D Scott, MD, J Finlayson, PhD, Office of Blood Research and Review, Center for Biologics Research and Review, Food and Drug Administration. Hospital Infections Program, National Center for Infectious Diseases; and an EIS Officer, CDC.
During 1985-1998, reports of RAEs associated with IGIV were infrequent; however, these events resulted in severe morbidity and mortality. Approximately 40% of the affected patients required dialysis, and the RAEs might have contributed to the death of 15% of patients who died despite therapy. Thus, health-care providers need to be aware of these events as they develop treatment plans for their patients.
The incidence of adverse events that occur during IGIV administration is usually reported as less than or equal to 5% but ranges from 1% to 15% (1). Reactions (e.g., fever, headache, myalgia, chills, nausea, and vomiting) often are related to the rate of IGIV infusion and tend to be mild to moderate and self-limited (2). The cause of these reactions may in some cases involve formation of IgG aggregates during manufacture or storage of IGIV preparations. To avoid aggregation, the purified Ig product is stabilized with glucose, maltose, glycine, sucrose, sorbitol, or albumin. Less common and more severe reactions include hypersensitivity and anaphylactoid reactions, thromboembolic events, and aseptic meningitis syndrome; the causes of these reactions are unknown.
Several mechanisms have been proposed for RAEs associated with IGIV administration. As early as 1940, studies documented the development of renal lesions, similar to those in the case-patients in this report, that resulted from intravenous administration of sucrose (3). Similar renal lesions can occur with parenteral mannitol, sorbitol, dextran, or hydroxyethyl starches (4). Additional mechanisms have been proposed (5); however, the exact pathophysiology of RAE development following administration of various IGIV preparations remains unclear.
The findings in this report have several limitations. First, the incidence of IGIV-associated RAEs cannot be determined. The extent of underreporting of these events is unknown, and nonproprietary data were unavailable to estimate the number of IGIV recipients during 1985-1998; however, thousands of persons probably receive IGIV annually, and the number of reported cases suggests that the incidence of RAEs is low. Second, reports of an association between RAEs and IGIV therapy are not sufficient evidence to prove that IGIV was the cause of the renal insufficiency or renal failure in these patients; however, the timing and biologic plausibility of a causal association are cause for concern. Additional studies are necessary to further evaluate this relation.
Although 90% of IGIV-associated RAEs in the United States have occurred with sucrose-containing IGIV preparations, caution is advised during administration of any IGIV product. All patients receiving IGIV therapy, particularly high-risk patients with pre-existing renal disease, diabetes mellitus, hypovolemia, sepsis, concomitant therapy with nephrotoxic agents, or aged greater than or equal to 65 years, should be monitored carefully for RAEs during and after IGIV administration. To decrease the risk for RAEs, renal function should be assessed before IGIV therapy is initiated and periodically thereafter. Manufacturer-recommended IGIV doses, concentrations, and infusion rates should not be exceeded and approved indications for IGIV therapy should be reviewed. IGIV infusions should be discontinued if renal function deteriorates. In addition, IGIV should be used judiciously and alternatives used when appropriate because of recent shortages (6).
To alert health-care providers to the risk for RAEs associated with IGIV, FDA has posted an advisory on MedWatch and on the Center for Biologics Research and Review's (CBER) World-Wide Web sites, and FDA has published a drug warning in its summer 1999 issue of FDA Medical Bulletin. Manufacturers are revising package inserts with new dosing recommendations and a warning of the risk involved in IGIV administration. Health-care providers are encouraged to report any RAE associated with the use of IGIV to the manufacturer or to MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, MD, 20852-9787; telephone (800) 332-1088; fax (800) 332-0178; World-Wide Web site http://www.fda.gov/medwatch, or to CDC's Hospital Infections Program, National Center for Infectious Diseases, (404) 639-6413.
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TABLE 1. Number of reported cases of renal adverse events (RAE) associated with immune globulin intravenous (IGIV) preparations -- United States, 1985-1999, ============================================================================================================================================= Grams No. (%) sucrose reported per gram Stabilizing of RAE of IgG substance Manufacturer* Distributor Product Approved indications ------------------------------------------------------------------------------------------------------------------------------------------- 59 (67%) 1.7 Sucrose Central Laboratory, Blood Novartis Sandoglobulin ® + PID& or ITP@ Transfusion Service, Pharmaceuticals Swiss Red Cross 19 (22%) 1.0 Sucrose or Centeon L.L.C. Centeon L.L.C. Gammar ® -P I.V. PID albumin and Gammar I.V.** 4 ( 5%) 0 Maltose or Bayer Corporation Bayer Corporation Gamimune-N PID, ITP, adult BMT++, glycine or pediatric HIV 3 ( 3%) 0 Glucose, Baxter Healthcare Corporation Baxter Gammagard S/D ®&& PID, ITP, or chronic albumin, or B-cell glycine lymphoblastic leukemia 2 ( 2%) Undetermined@@ 1 ( 1%) 1.7 Sucrose Central Laboratory, Blood American Red Cross Panglobulin ® + PID or ITP Transfusion Service, Swiss Red Cross 0 ( 0 ) 0 Sorbitol or Alpha Therapeutic Alpha Therapeutic Venoglobulin-s ® and PID, ITP, or Kawasaki aluminum Corporation Corporation Venoglobulin-I ® syndrome 0 ( 0 ) 0 Glucose, Baxter Healthcare American Red Cross Polygam S/D ®&& PID, ITP, or chronic albumin, or Corporation B-cell glycine lymphoblastic leukemia 0 ( 0 ) 0 Glucose Oesterreichisches Institut Immuno U.S. Inc. Iveegam ® PID or Kawasaki fuer Haemoderivative syndrome Ges.m.b.H (O.I.H.) ------------------------------------------------------------------------------------------------------------------------------------------- * Use of trade names and commercial sources is for identification only and does not imply endorsement by U. S. Department of Health and Human Services or CDC. + Sandoglobulin ® and Panglobulin ® use the same formulation. & Primary immunodeficiency. @ Immune-mediated thrombocytopenia. ** Gammar I.V. was withdrawn from the market after the introduction of Gammar-P I.V. ++ Bone marrow transplantation. && Gammagard S/D ® and Polygam S/D ® use the same formulation. @@ Two reactions were associated with unspecified IGIV. =============================================================================================================================================
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