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Published ahead of print on April 26, 2006
Clin J Am Soc Nephrol 1: 844-852, 2006
© 2006 American Society of Nephrology
doi: 10.2215/CJN.01701105
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Renal Transplantation

Safety and Adverse Events Profiles of Intravenous Gammaglobulin Products Used for Immunomodulation: A Single-Center Experience

Ashley A. Vo*, Vinh Cam*, Mieko Toyoda{dagger}, Dechu P. Puliyanda*, Marina Lukovsky*, Suphamai Bunnapradist*, Alice Peng*, Kai Yang{ddagger}, and Stanley C. Jordan*,{dagger}

* Comprehensive Transplant Center, {dagger} Transplant Immunology Laboratory, and {ddagger} Department of Medical Genetics, Cedars-Sinai Medical Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California

Address correspondence to: Dr. Ashley A. Vo, Center for Kidney Diseases & Transplantation, Cedars-Sinai Medical Center, 8635 W. 3rd Street, Suite 590W, Los Angeles, CA 90048. Phone: 310-423-2967; Fax: 310-423-6369; E-mail: ashley.vo{at}cshs.org


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Intravenous Ig (IVIg) products are used in various medical conditions. Differences in excipients account for most adverse events (AE). Reports of complications including acute myocardial infarction (AMI) and acute renal failure (ARF) have emerged. Herein is described one institution’s experience with IVIg-related complications. This study is a retrospective analysis of infusion-related AE that are associated with various IVIg products. Infusion-related AE were monitored during and after the administration of three IVIg products: Gamimune-N 10% (n = 76), Polygam (n = 105), and Carimune (n = 98). AE segregated to specific IVIg products. No patients who received Gamimune-N experienced AMI or ARF. Five (4.7%) patients (P < 0.01) in the Polygam group experienced AMI. Eight (8.2%) patients (P < 0.0001) in the Carimune group developed ARF. IVIg was safe to give on hemodialysis. IVIg products differ in osmolality, pH, and sugar and sodium content; this results in specific AE. Polygam resulted in no ARF but an increase in AMI. Carimune products at 9% concentration resulted in an increase in ARF. Gamimune-N 10% and other IVIg products were frequently associated with headaches. Administration of IVIg to patients who are on hemodialysis seems to be safe and effective.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Intravenous Ig (IVIg) products initially were developed for treatment of immune deficiency disorders. The immunomodulatory effects of IVIg rapidly led to a broader usage of IVIg in autoimmune and inflammatory disorders, usually at much higher doses (1). More recently, IVIg has been used in kidney transplantation for decreasing panel reactive antibodies in highly sensitized patients (2) and for the treatment of antibody-mediated rejection (AMR) (3–5). Although many consider that all IVIg products are similar, it now is clear that they differ greatly in regard to excipient compounds and related adverse effects (6). Proper product selection for each patient is critical because the adverse effect profiles of each formulation differ on the basis of the excipient. Certain patients, such as those with diabetes or those who are at risk for renal failure and/or heart disease, may not tolerate particular IVIg formulations. Product features that affect tolerability include volume load, infusion rates, osmolality, pH, and sodium or sugar content. Specific adverse effects seem to correlate with product excipient (sucrose/sodium) and osmolality. Therefore, there is a need to define better the relationship among various IVIg preparations, patient risk factors, and specific adverse effects.

Twenty-nine cases of thrombotic complications with the use of IVIg have been reported and include acute myocardial infarction (AMI), cerebral infarction, pulmonary embolism (PE), deep venous thrombosis (DVT), hepatic veno-occlusive disease, and spinal cord ischemia (7–12). No correlation yet has been made between particular IVIg products and thrombotic complications. Many papers suggest that the thrombosis was incited specifically from the gammaglobulin incipient, contaminants such as activated factor XI, or a high rate of drug infusion (13,14). There have been attempts to delineate the mechanism of IVIg-induced thrombosis (7,15–18), but no clear cause has been established.

Another known complication of IVIg is acute renal failure (ARF) (19). Previous reports seem to suggest that sucrose-based products are commonly associated with ARF (19–22).

Here, we report on the adverse effect profiles of three products that were used at Cedars-Sinai Medical Center between 1997 and 2004. This study represents a nonrandomized, retrospective study of patients who received those IVIg products during that period. Specific product use was based on pharmacy purchasing practices. Furthermore, no protocols for premedication before IVIg infusion to reduce adverse effects have been established. Here, we discuss procedures that were developed at our center to attempt to decrease adverse events (AE) that are related to IVIg infusion.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patients and AE
After approval was obtained from the Institutional Review Board, 279 patients who received IVIg at Cedars-Sinai Medical Center between 1997 and 2004 were identified for retrospective analysis. Seventy-six patients received Gamimune-N 10% (Bayer Biologicals, West Haven, CT; October 1997 to June 2000); 105 patients received Polygam (Baxter Inc., Los Angeles, CA; April 2000 to February 2002), and 98 patients received Carimune (ZLB Biologicals, Berne, Switzerland; March 2002 to September 2004). A retrospective analysis of significant AE that were associated with various IVIg products was performed. Premedication protocols and product selection paradigms were developed from the data and applied to minimize serious AE. Postimplementation monitoring of AE then was recorded.

Any documentation of AMI, ARF, hypotension, or death within 72 h of administration was considered related to IVIg infusion. In addition, reports of other common adverse effects of headaches, flushing, pruritus, or rash were noted. To determine whether there was causality, we calculated an Adverse Drug Reaction score on the basis of 10 questions that were developed by Naranjo et al. (23) by two independent reviewers. A score of 9 of 13 or higher was considered highly probable, whereas 5 to 8 was moderate and 1 to 4 was unlikely.

Once an AE was identified and found to be specific to a particular IVIg formulation with probable causality, product selection paradigms and premedication protocols were developed and applied to minimize AE. After these changes were made in 2002, postimplementation monitoring for AE was reported.

Three primary areas of risk for IVIg infusions were identified. These were cardiovascular disease, renal disease, and propensity for hypercoagulation. Risk factors for AMI were based on National Cholesterol Education Program (NCEP) III guidelines (24) and included age (>50 for men, >60 for women), history of AMI, hypertension, hypercholesterolemia, diabetes, obesity, or previous evidence of peripheral vascular disease (e.g., stroke, atherosclerotic aortoiliac disease). Risk factors for ARF included (1) a history of diabetes, (2) history of cardiovascular disease and congestive heart failure, (3) history of elevated serum creatinine (>2.0 mg/dl), and (4) advanced age (>70 yr).

Statistical Analyses
Statistical analysis was performed using the {chi}2 test. AE in each IVIg group were analyzed and compared. Differences were considered significant at the 0.05 level.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Product Composition and Relations to AE
Gamimune-N 10%, Carimune, and Polygam were the three IVIg products that were used at Cedars-Sinai Medical Center during the study period. Product selection was based on pharmacy purchasing practices. Table 1 identifies the most common IVIg products that were commercially available in the United States during the study period and their constituent makeup. Gamimune-N-10% excipient (Glycine) had the least amount of sodium chloride, had no sucrose, and is isosmolar (274 mOsm/L at 10%). Carimune is a lyophilized powder that can be reconstituted in sterile water or normal saline. It contains 1.67 g sucrose/g IVIg and at 12% in saline has an osmolality of 1074 mOsm/L and when reconstituted in sterile water has an osmolality of 768 mOsm/L. Polygam 10% also is lyophilized and can be reconstituted in sterile water or normal saline. If reconstituted in NS, Polygam 10% has an osmolality of 1250 mOsm/L. In fact, at 10%, the osmolality is identical to a 2% saline infusion.


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  		Table 1. Product characteristics

 
The indications for use of IVIg in the 279 patients were hypogammaglobulinemia, idiopathic thrombocytic purpura, treatment of acute AMR, polyneuropathy, hematologic malignancy, and desensitization of highly HLA-sensitized patients who were awaiting solid-organ transplantation. Ages of recipients were 4 mo to 92 yr, and there was equal gender distribution among groups. Approximately half of the patients in each group had risk factors for heart disease. Dosages received were between 0.5 and 2 g/kg (Table 2). All IVIg products were infused at rates recommended by the manufacturer. For Gamimune-N 10% the start infusion rate was 0.01 to 0.02 ml/kg per min for 30 min. If no adverse reactions occurred, then the rate was increased gradually to a maximum of 0.08 ml/kg per min. For Carimune, the start infusion rate was 30 ml/h for 30 min, then 60 ml/h for 30 min, and was increased as tolerated by 30 ml/h every 15 min to a maximum rate of 120 ml/h. For Polygam, the start infusion rate was 0.5 ml/kg per h and was increased slowly to a maximum rate of 4 ml/kg per h if well tolerated in patients with thrombotic risk factors such as coronary artery disease, hypertension and cerebrovascular disease, and diabetes.


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  		Table 2. Demographics

 
Significant AE (AMI and ARF) were noted only in the Polygam (P < 0.01) and Carimune (P < 0.0001) groups, respectively. Headache was the only notable adverse effect of Gamimune-N 10% infusion (52%) but also occurred in other products. In our experience, headaches were self-limited and did not require additional investigation (computed tomography or magnetic resonance imaging) and usually respond to acetaminophen. Patient demographics are shown in Table 2. The distribution of AE and significant AE is shown in Table 3.


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  		Table 3. AE and SAEa

 
IVIg and AMI
Five cases of AMI were noted in patients who received IVIg. The ages ranged from 34 to 72 yr (Table 4). All five patients had risk factors for cardiac disease. The number of IVIg treatments that were received before the event ranged from one to eight. Each patient developed symptoms during or shortly (3 to 5 h) after IVIg infusion, which included shortness of breath and chest pain. The diagnosis of AMI was confirmed by electrocardiogram and/or troponin elevations. In four cases, AMI prolonged hospitalization. In the fifth case, the diagnosis of AMI resulted in the hospitalization after the patient received IVIg as an outpatient infusion. All patients recovered without significant long-term effects. Because AMI occurred only with Polygam, these were reported to the manufacturer and the Food and Drug Administration MedWatch. This resulted in a "Dear Doctor Letter" regarding the risk for thrombotic events that were associated with Polygam (25).


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  		Table 4. Myocardial infarction in patients who received Polygama

 
Polygam’s excipient is a sodium chloride solution with an approximate osmolality of 1250 mOsm/L at 10%. Analysis using the Naranjo algorithm yielded a moderate probability of causality. The risk for development of thrombotic events with Polygam also was statistically significantly different when compared with the other IVIg products (P < 0.01). We hypothesized that the salt-based high-viscosity vehicle of this product likely was responsible for initiation of the thrombotic event seen (AMI). Therefore, steps were taken to change the standard default IVIg formulation to one of a non–sodium-based lower osmolality solution (530 mOsm/L; Carimune 9%) or 309 mOsm/L (Gamimune-N 10%). In addition, premedication with aspirin as well as an option to hydrate patients was suggested. Because these changes were implemented and after approximately 250 IVIg doses, no further cases of AMI have been reported.

IVIg and ARF
After the change from routine use of Polygam to that of either Carimune or Gamimune-N 10%, eight cases of ARF were seen. ARF occurred only in patients who received the sucrose-containing IVIg (Carimune; P < 0.0001; see Tables 2 and 3). A Naranjo algorithm analysis also yielded a moderate probability of causality (score 6). All eight patients had identifiable risk factors for ARF. Five of the eight patients had a history of chronic kidney disease or had received a kidney transplant, and the other three had diabetes, congestive heart failure, or recent IV contrast dye administration. Six of eight patients had significant renal dysfunction with doubling of serum creatinine after IVIg administration, with six requiring hemodialysis. However, recovery of renal function occurred in all patients within 2 mo. A renal allograft biopsy was done in one patient who had marked delayed graft function and received IVIg before kidney transplantation for a positive cross-match. Results were notable for acute tubular necrosis and marked vacuolization of proximal tubular cells that were attributed to IVIg/sucrose. Table 5 shows the characteristics of patients who developed ARF after sucrose-containing IVIg infusions. Figure 1 shows an electron micrograph demonstrating vacuolization in renal tubules in a patient with osmotic nephropathy after sucrose-containing IVIg infusion.


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  		Table 5. IVIg and renal failurea

 

Figure 1
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  		Figure 1. Sucrose-containing intravenous Ig (IVIg) induced osmotic nephropathy. Electron micrograph from a patient with osmotic nephropathy induced by sucrose-containing IVIg. Vacuoles are noted in the renal tubular cells and are indicative of osmotic injury by sucrose. The patient received a 12% solution. Shortly thereafter, the creatinine rose to 8 mg/dl, and the patient required dialysis.

 
After noting the relationship between ARF and previous kidney dysfunction in patients who received Carimune, all patients who receive IVIg now are required to have a preinfusion baseline serum creatinine and screening for risk factors for renal disease. Subsequently, avoidance of sucrose-based products in patients who are at risk by specifically selecting non–sucrose-containing isosmolar products has resulted in no additional cases of ARF.

IVIg Infusions in ESRD Patients on Hemodialysis
Administering IVIg is challenging in patients who are unable to tolerate high volumes or solute loads, such as those with congestive heart failure and ESRD. This is particularly important for prekidney transplant recipients, who usually are dialysis dependent and prone to volume overload. Like any other blood product, we infused IVIg (Gamimune-N 10%) during hemodialysis and compared this with placebo (albumin 0.1%) as part of the NIH IG02 study (26). More than 300 infusions of IVIg were given to 50 patients and compared with an equivalent number of placebo infusions to 52 patients. Analysis showed that IVIg was well tolerated with a low incidence of volume overload, pruritus, and rash. The number of minor (7.7% in IVIg versus 7.5% in albumin) and significant (0.3% IVIg versus 2.8% albumin) AE were comparable to or less than that of placebo.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
The use of IVIg products for the treatment of autoimmune and inflammatory disorders has increased dramatically in the past decade. In addition, recent data suggest that IVIg products are useful in the treatment of highly HLA-sensitized patients who are awaiting transplantation and for the management of viral infections and AMR (26–28). The use of higher doses, concentrations, and rapid rates of infusion of IVIg products has resulted in higher rates of infusion-related complications that, at first, were not anticipated and were poorly understood.

It now is very clear that IVIg products vary considerably in their composition and that these differences have clinical implications (29). All contain IgG molecules (90 to 99%) but differ considerably in excipient. IVIg products differ in osmolality, pH, and sugar and sodium content, and this is postulated to result in product-specific adverse effects (6). The use of Polygam, which contains high concentrations of sodium at 10%, was associated with five cases of AMI. MI is a known complication of IVIg infusion (10,14). Our findings suggest that this may be due to the excipient (sodium chloride) and not incipient as evidenced by the lack of events with sucrose-based and isosmolar products. In addition, these events did not occur when Polygam was administered to patients who were on hemodialysis, suggesting that reductions in sodium content and/or heparinization was protective. Furthermore, it seems that viscosity of the diluent may be a factor that increases the risk for thrombosis as Polygam 10% had a much higher osmolality than Carimune 9% or Gamimune-N 10%. Previous reports have shown that IVIg increases blood viscosity (30), and it is possible that it contributes to the thrombogenic nature of sodium-based IVIg formulations. Other possible explanations for the prothrombotic effects of IVIg suggest that there might be an effect on platelet aggregation. However, Vassilev et al. (31) showed that IVIg actually contains antibodies that are inhibitory to inducers of platelet aggregation. Data from Abe et al. (32) also support an antithrombotic effect of IVIg in Kawasaki disease.

The antiplatelet agent aspirin may decrease the risk for myocardial events during IVIg infusion. Whether Ig causes increased platelet aggregation in vivo is unknown but seems unlikely on the basis of published data. This is consistent with previous experiments in which IVIg did not cause an increase in platelet ADP release and actually can reduce aggregation that is seen with other agents (7,11). However, unless there is a contraindication, we would recommend that patients who are at higher risk for thrombosis or MI receive aspirin and hydration (250 ml of 0.9 normal saline over 30 min) before IVIg infusion. There are no data to support any particular premedication regimen. However, our experience supports the pre-IVIg infusion use of Benadryl 25 to 50 mg orally or intravenously, Tylenol 650 mg orally, or aspirin 325 mg orally and Solu-Medrol 40 mg intravenously 30 min before the infusion to reduce infusion-related adverse effects. Selection of products with lower osmolality or reduction in osmolality of sodium-based products by reducing the concentration (from 10 to 5%) also should be considered.

The use of Carimune resulted in an increased incidence of ARF. This finding coincides with previously published reports that 90% of ARF occurred with sucrose-based products (21). It suggests that toxicity to proximal tubule cells as a result of a high osmotic load of sucrose and leading to vacuolization is a likely mechanism (33). This pathology (Figure 1) was seen in one patient who underwent renal biopsy after rapid onset of renal dysfunction after sucrose-based IVIg infusion. Fortunately, recovery is the rule as all eight patients eventually regained baseline kidney function as determined by serum creatinine. Nonetheless, all patients should be screened for renal disease with at least a serum creatinine before IVIg administration. Caution should be exercised for those who are at risk for renal failure, such as patients with diabetes or congestive heart failure. Avoidance of sucrose-based IVIg products under these circumstances is strongly recommended.

Administration of IVIg to patients who are on hemodialysis seems to be safe and effective, with minimal adverse effects and rare significant AE. In addition to removal of potential excessive volume and solutes such as sucrose and sodium, hemodialysis patients routinely are heparinized, which limits thrombotic complications. Therefore, we believe that the use of all IVIg products is safe when given to patients who are on hemodialysis.

The infusion of the isosmolar IVIg product Gamimune-N 10% was not associated with AMI or ARF but did cause headache (52%), not unlike Carimune (50%) and Polygam (50%). Slowing the infusion rate and extending the administration time to over 8 h significantly decreased the incidence of headache as well as other less severe adverse effects.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
It is important to understand that all IVIg products are not alike. They differ in salt and sugar content, pH, and osmolality. Careful attention to the products that are provided by an institution’s pharmacy is critical to avoid excipient-related adverse effects. On the basis of our experience, all IVIg products can be administered safely if adverse effect profiles are recognized and appropriate patient selection and premedications are given. Because the use and indications for IVIg continue to expand and higher doses and volumes are mandated for autoimmune and inflammatory disorders, it is critical to be aware of the potential adverse effects that are associated with specific products and, more important, how to prevent them.


   Acknowledgments
 
This work was supported by the Joyce Jillson Fund for Kidney Transplantation. S.C.J. is the recipient of research grant support from Talecris Inc. and ZLB-Berhing, Inc.

We express our collective gratitude to Eden Garcia for help in preparation of this manuscript.


   Footnotes
 
Published online ahead of print. Publication date available at www.cjasn.org.

Received November 10, 2005. Accepted March 12, 2006.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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