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

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

Ashley A. Vo,* Vinh Cam,* Mieko Toyoda,† Dechu P. Puliyanda,* Marina Lukovsky,* Suphamai Bunnapradist,* Alice Peng,* Kai Yang,‡ and Stanley C. Jordan*† *Comprehensive Transplant Center, †Transplant Immunology Laboratory, and ‡Department of Medical Genetics, Cedars-Sinai Medical Center, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California

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 AE .(98 ؍ and Carimune (n ,(105 ؍ Polygam (n ,(76 ؍ after the administration of three IVIg products: Gamimune-N 10% (n 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. Clin J Am Soc Nephrol 1: 844–852, 2006. doi: 10.2215/CJN.01701105

ntravenous Ig (IVIg) products initially were developed for define better the relationship among various IVIg preparations, treatment of immune deficiency disorders. The immuno- patient risk factors, and specific adverse effects. I modulatory effects of IVIg rapidly led to a broader usage Twenty-nine cases of thrombotic complications with the use of IVIg in autoimmune and inflammatory disorders, usually at of IVIg have been reported and include acute myocardial in- much higher doses (1). More recently, IVIg has been used in farction (AMI), cerebral infarction, pulmonary embolism (PE), kidney transplantation for decreasing panel reactive antibodies deep venous thrombosis (DVT), hepatic veno-occlusive disease, in highly sensitized patients (2) and for the treatment of anti- and spinal cord ischemia (7–12). No correlation yet has been body-mediated rejection (AMR) (3–5). Although many consider made between particular IVIg products and thrombotic com- that all IVIg products are similar, it now is clear that they differ plications. Many papers suggest that the thrombosis was in- greatly in regard to excipient compounds and related adverse cited specifically from the gammaglobulin incipient, contami- effects (6). Proper product selection for each patient is critical nants such as activated factor XI, or a high rate of drug infusion because the adverse effect profiles of each formulation differ on (13,14). There have been attempts to delineate the mechanism the basis of the excipient. Certain patients, such as those with of IVIg-induced thrombosis (7,15–18), but no clear cause has diabetes or those who are at risk for renal failure and/or heart been established. disease, may not tolerate particular IVIg formulations. Product Another known complication of IVIg is acute renal failure features that affect tolerability include volume load, infusion (ARF) (19). Previous reports seem to suggest that sucrose-based rates, osmolality, pH, and sodium or sugar content. Specific products are commonly associated with ARF (19–22). adverse effects seem to correlate with product excipient (su- Here, we report on the adverse effect profiles of three prod- crose/sodium) and osmolality. Therefore, there is a need to ucts 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 phar- Received November 10, 2005. Accepted March 12, 2006. macy purchasing practices. Furthermore, no protocols for pre- Published online ahead of print. Publication date available at www.cjasn.org. medication before IVIg infusion to reduce adverse effects have Address correspondence to: Dr. Ashley A. Vo, Center for Kidney Diseases & been established. Here, we discuss procedures that were devel- 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: oped at our center to attempt to decrease adverse events (AE) [email protected] that are related to IVIg infusion.

Materials and Methods Statistical Analyses Patients and AE Statistical analysis was performed using the ␹2 test. AE in each IVIg After approval was obtained from the Institutional Review Board, group were analyzed and compared. Differences were considered sig- 279 patients who received IVIg at Cedars-Sinai Medical Center between nificant at the 0.05 level. 1997 and 2004 were identified for retrospective analysis. Seventy-six patients received Gamimune-N 10% (Bayer Biologicals, West Haven, Results CT; October 1997 to June 2000); 105 patients received Polygam (Baxter Product Composition and Relations to AE Inc., Los Angeles, CA; April 2000 to February 2002), and 98 patients Gamimune-N 10%, Carimune, and Polygam were the three received Carimune (ZLB Biologicals, Berne, Switzerland; March 2002 to IVIg products that were used at Cedars-Sinai Medical Center September 2004). A retrospective analysis of significant AE that were during the study period. Product selection was based on phar- associated with various IVIg products was performed. Premedication macy purchasing practices. Table 1 identifies the most common protocols and product selection paradigms were developed from the data and applied to minimize serious AE. Postimplementation moni- IVIg products that were commercially available in the United toring of AE then was recorded. States during the study period and their constituent makeup. Any documentation of AMI, ARF, hypotension, or death within 72 h Gamimune-N-10% excipient (Glycine) had the least amount of of administration was considered related to IVIg infusion. In addition, sodium chloride, had no sucrose, and is isosmolar (274 reports of other common adverse effects of headaches, flushing, pruri- mOsm/L at 10%). Carimune is a lyophilized powder that can tus, or rash were noted. To determine whether there was causality, we be reconstituted in sterile water or normal saline. It contains calculated an Adverse Drug Reaction score on the basis of 10 questions 1.67 g sucrose/g IVIg and at 12% in saline has an osmolality of that were developed by Naranjo et al. (23) by two independent review- 1074 mOsm/L and when reconstituted in sterile water has an ers. A score of 9 of 13 or higher was considered highly probable, osmolality of 768 mOsm/L. Polygam 10% also is lyophilized whereas 5 to 8 was moderate and 1 to 4 was unlikely. and can be reconstituted in sterile water or normal saline. If Once an AE was identified and found to be specific to a particular reconstituted in NS, Polygam 10% has an osmolality of 1250 IVIg formulation with probable causality, product selection paradigms mOsm/L. In fact, at 10%, the osmolality is identical to a 2% and premedication protocols were developed and applied to minimize saline infusion. AE. After these changes were made in 2002, postimplementation mon- The indications for use of IVIg in the 279 patients were itoring for AE was reported. hypogammaglobulinemia, idiopathic thrombocytic purpura, Three primary areas of risk for IVIg infusions were identified. These treatment of acute AMR, polyneuropathy, hematologic malig- were cardiovascular disease, renal disease, and propensity for hyper- nancy, and desensitization of highly HLA-sensitized patients coagulation. Risk factors for AMI were based on National Cholesterol Education Program (NCEP) III guidelines (24) and included age (Ͼ50 who were awaiting solid-organ transplantation. Ages of recip- for men, Ͼ60 for women), history of AMI, hypertension, hypercholes- ients were 4 mo to 92 yr, and there was equal gender distribu- terolemia, diabetes, obesity, or previous evidence of peripheral vascu- tion among groups. Approximately half of the patients in each lar disease (e.g., stroke, atherosclerotic aortoiliac disease). Risk factors group had risk factors for heart disease. Dosages received were for ARF included (1) a history of diabetes, (2) history of cardiovascular between 0.5 and 2 g/kg (Table 2). All IVIg products were disease and congestive heart failure, (3) history of elevated serum infused at rates recommended by the manufacturer. For creatinine (Ͼ2.0 mg/dl), and (4) advanced age (Ͼ70 yr). Gamimune-N 10% the start infusion rate was 0.01 to 0.02 ml/kg

Table 1. Product characteristics

Preparation/ Sodium Content Concentrations Manufacturer Osmolality Sucrose Content (mEq/L at 5% Available (g/g protein) concentration)

Gamimune-N 10% Bayer 309 mOsm/kg solvent (water) for 0 Trace N/5%, 10% 5% solution; 274 mOsm/kg solvent (water) for 10% solution Gammagard/5%, 10% Hyland Division of 636 mOsm/kg solvent (water) for 0 147 Baxter Healthcare 5% solution; 1250 mOsm/kg solvent (water) for 10% solution Polygam/5%, 10% Hyland Division of 590 mOsm/kg solvent (water) for 0 147 Baxter Healthcare 5% solution; 1179 mOsm/kg solvent (water) for 10% solution Carimune 3%, 6%, ZLB Central 3%, 192 mOsm/kg; 6%, 384 1.67 1.3 9%, 12% Laboratory mOsm/kg; 9%, 576 mOsm/kg; 12%, 768 mOsm/kg solvent (water) 846 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 1: 844–852, 2006

Table 2. Demographics

Carimune Gamimune-N Polygam (n ϭ 98) (n ϭ 76) (n ϭ 105)

Gender (%) male 48 41 51 female 52 59 49 Indications (%) desensitization 77 66 37 autoimmune 21 26 55 immune deficiency 2 8 8 Age range 2 to 84 yr 15 to 75 yr 4 mo to 92 yr Cardiovascular risk factorsa (%) 56 50 40 Dose (g/kg; average Ϯ SD) 1.1 Ϯ 0.47 2.0 1.25 Ϯ 0.63

aCoronary heart disease and coronary heart disease risk equivalents as defined by National Cholesterol Education Program (NCEP) III. per min for 30 min. If no adverse reactions occurred, then the risk factors for cardiac disease. The number of IVIg treatments rate was increased gradually to a maximum of 0.08 ml/kg per that were received before the event ranged from one to eight. min. For Carimune, the start infusion rate was 30 ml/h for 30 Each patient developed symptoms during or shortly (3 to 5 h) min, then 60 ml/h for 30 min, and was increased as tolerated by after IVIg infusion, which included shortness of breath and 30 ml/h every 15 min to a maximum rate of 120 ml/h. For chest pain. The diagnosis of AMI was confirmed by electrocar- Polygam, the start infusion rate was 0.5 ml/kg per h and was diogram and/or troponin elevations. In four cases, AMI pro- increased slowly to a maximum rate of 4 ml/kg per h if well longed hospitalization. In the fifth case, the diagnosis of AMI tolerated in patients with thrombotic risk factors such as coro- resulted in the hospitalization after the patient received IVIg as nary artery disease, hypertension and cerebrovascular disease, an outpatient infusion. All patients recovered without signifi- and diabetes. cant long-term effects. Because AMI occurred only with Po- Significant AE (AMI and ARF) were noted only in the Po- lygam, these were reported to the manufacturer and the Food lygam (P Ͻ 0.01) and Carimune (P Ͻ 0.0001) groups, respec- and Drug Administration MedWatch. This resulted in a “Dear tively. Headache was the only notable adverse effect of Doctor Letter” regarding the risk for thrombotic events that Gamimune-N 10% infusion (52%) but also occurred in other were associated with Polygam (25). products. In our experience, headaches were self-limited and Polygam’s excipient is a sodium chloride solution with an did not require additional investigation (computed tomogra- phy or magnetic resonance imaging) and usually respond to approximate osmolality of 1250 mOsm/L at 10%. Analysis acetaminophen. Patient demographics are shown in Table 2. using the Naranjo algorithm yielded a moderate probability of The distribution of AE and significant AE is shown in Table 3. causality. The risk for development of thrombotic events with Polygam also was statistically significantly different when com- IVIg and AMI pared with the other IVIg products (P Ͻ 0.01). We hypothesized Five cases of AMI were noted in patients who received IVIg. that the salt-based high-viscosity vehicle of this product likely The ages ranged from 34 to 72 yr (Table 4). All five patients had was responsible for initiation of the thrombotic event seen

Table 3. AE and SAEa

Carimune Gamimune-N Polygam (n ϭ 98) (n ϭ 76) (n ϭ 105)

%AEorSAE n ϭ 8 (SAE) N/A n ϭ 5 (SAE) Gender 3 male/5 female N/A 2 male/3 female Age range (yr) 39 to 79 15 to 75 34 to 77 Type of AE/SAE thrombotic 0 0 5 (4.7%); P Ͻ 0.01 ARF 8 (8.2%); P Ͻ 0.001 0 0 other (headache) 49 (50%) 39 (52%) 52 (50%) Doses 2 g/kg ϭ 7 patients 2 g/kg 2 g/kg ϭ 4 patients 1 g/kg ϭ 1 patient 1 g/kg ϭ 1 patient

aAE, adverse events; ARF, acute renal failure; SAE, significant adverse events. lnJA o eho :8482 2006 844–852, 1: Nephrol Soc Am J Clin

Table 4. Myocardial infarction in patients who received Polygama

Time Correlation between Patient Indication Total No. of Rate of IVIg Comorbidities Dose of IVIg IVIg Infusion and Onset of Age/Gender for IVIg IVIg Doses Infusionb Symptoms

54/male AIDS, non-Hodgkin’s ITP 2 (inpatient) Day 1 ϭ 70 g (1 g/kg; 1400 over 12 h, 1.7 Day 2: 5 h into IVIg infusion lymphoma, aortic stenosis ml of 5%) ml/kg per h developed SOB, no N/V, Day 2 ϭ 70 g (700 ml of over 6 h, 1.7 CP. ECG changes, elevated 10%) ml/kg per h troponins, transferred to ICU. Discharge home 10 d later 49/female Pauciimmune S/p kidney transplant with 1 (inpatient) 140 g (2 g/kg; 1400 ml of over 5 h, 3.9 At the end of infusion, glomerulonephritis, ESRD, increasing SCr 10%) ml/kg per h patient developed CP S/p kidney transplant, radiating to left arm, N/V, hypercholesterolemia SOB. ST elevations, elevated troponin. Transferred to ICU. Discharged home 6 d later 34/female SLE, ESRD S/p kidney To reduce PRA 8 (every month in the 100 g (2 g/kg; 1000 ml of over 6 h, 3.4 5 h after start of infusion,

transplant outpatient procedure 10%) ml/kg per h developed CP, radiating 847 to Immunomodulation for IVIg of Events Adverse and Safety center) the jaw, SOB. Elevated troponins. Discharged home 4 d later 77/female CAD, CHF, MVR, pacemaker ITP 2.5 (inpatient) Day 1 ϭ 66 g (1 g/kg; 660 over 6 h, 1.7 Day 2: 3 h after start of placement 1 mo ago, ml of 10%) ml/kg per h infusion developed diabetes, hypertension Day 2 ϭ 63 g (1 g/kg; 630 over 6 h, 0.8 substernal chest pain, ml of 10%) ml/kg per h diaphoresis, no SOB, N/V. Day 3 ϭ 31 g (0.5 g/kg; 310 ECG changes, elevated ml of 10%) troponins. Day 3: No complications. Underwent scheduled MVR next day 69/male Bronchiectasis, recurrent To maintain antibacterial/ 1 (inpatient) 70 g (1 g/kg; 700 ml of 10%) over 6 h, 1.7 Elevated troponin, respiratory infections, H/o viral antibody titers to ml/kg per h underwent emergent decreased IgG levels with prevent recurrent stenting normal antigen response infections

a CAD, coronary artery disease; CHF, congestive heart failure; CP, chest pain; ECG, electrocardiogram; H/o, history of; ICU, intensive care unit; ITP, idiopathic thrombocytopenic purpura; IVIg, intravenous Ig; MVR, mitral valve repair; N/V, nausea and vomiting; PRA, panel reactive antibodies; SCr, serum creatinine; SLE, systemic lupus erythematosus; SOB, shortness of breath. b Polygam S/D 5% solution should be infused at an initial rate of 0.5 ml/kg per h. If this rate causes the patient no distress, then the rate may be increased gradually up to 4 ml/kg per h. The 10% solution can be started at 0.5 ml/kg per h up to a maximum of 8 ml/kg per h. 848 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 1: 844–852, 2006

(AMI). Therefore, steps were taken to change the standard versus 2.8% albumin) AE were comparable to or less than that of default IVIg formulation to one of a non–sodium-based lower placebo. osmolality solution (530 mOsm/L; Carimune 9%) or 309 mOsm/L (Gamimune-N 10%). In addition, premedication with Discussion aspirin as well as an option to hydrate patients was suggested. The use of IVIg products for the treatment of autoimmune Because these changes were implemented and after approxi- and inflammatory disorders has increased dramatically in the mately 250 IVIg doses, no further cases of AMI have been past decade. In addition, recent data suggest that IVIg products reported. 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, IVIg and ARF concentrations, and rapid rates of infusion of IVIg products has After the change from routine use of Polygam to that of either resulted in higher rates of infusion-related complications that, Carimune or Gamimune-N 10%, eight cases of ARF were seen. at first, were not anticipated and were poorly understood. ARF occurred only in patients who received the sucrose-con- It now is very clear that IVIg products vary considerably in taining IVIg (Carimune; P Ͻ 0.0001; see Tables 2 and 3). A their composition and that these differences have clinical im- Naranjo algorithm analysis also yielded a moderate probability plications (29). All contain IgG molecules (90 to 99%) but differ of causality (score 6). All eight patients had identifiable risk considerably in excipient. IVIg products differ in osmolality, factors for ARF. Five of the eight patients had a history of pH, and sugar and sodium content, and this is postulated to chronic kidney disease or had received a kidney transplant, and result in product-specific adverse effects (6). The use of Po- the other three had diabetes, congestive heart failure, or recent lygam, which contains high concentrations of sodium at 10%, IV contrast dye administration. Six of eight patients had signif- was associated with five cases of AMI. MI is a known compli- icant renal dysfunction with doubling of serum creatinine after cation of IVIg infusion (10,14). Our findings suggest that this IVIg administration, with six requiring hemodialysis. However, may be due to the excipient (sodium chloride) and not incipient recovery of renal function occurred in all patients within 2 mo. as evidenced by the lack of events with sucrose-based and A renal allograft biopsy was done in one patient who had isosmolar products. In addition, these events did not occur marked delayed graft function and received IVIg before kidney when Polygam was administered to patients who were on transplantation for a positive cross-match. Results were notable hemodialysis, suggesting that reductions in sodium content for acute tubular necrosis and marked vacuolization of proxi- and/or heparinization was protective. Furthermore, it seems mal tubular cells that were attributed to IVIg/sucrose. Table 5 that viscosity of the diluent may be a factor that increases the shows the characteristics of patients who developed ARF after risk for thrombosis as Polygam 10% had a much higher osmo- sucrose-containing IVIg infusions. Figure 1 shows an electron lality than Carimune 9% or Gamimune-N 10%. Previous re- micrograph demonstrating vacuolization in renal tubules in a ports have shown that IVIg increases blood viscosity (30), and patient with osmotic nephropathy after sucrose-containing IVIg it is possible that it contributes to the thrombogenic nature of infusion. sodium-based IVIg formulations. Other possible explanations After noting the relationship between ARF and previous for the prothrombotic effects of IVIg suggest that there might be kidney dysfunction in patients who received Carimune, all an effect on platelet aggregation. However, Vassilev et al. (31) patients who receive IVIg now are required to have a preinfu- showed that IVIg actually contains antibodies that are inhibi- sion baseline serum creatinine and screening for risk factors for tory to inducers of platelet aggregation. Data from Abe et al. renal disease. Subsequently, avoidance of sucrose-based prod- (32) also support an antithrombotic effect of IVIg in Kawasaki ucts in patients who are at risk by specifically selecting non– disease. sucrose-containing isosmolar products has resulted in no addi- The antiplatelet agent aspirin may decrease the risk for myo- tional cases of ARF. cardial events during IVIg infusion. Whether Ig causes increased platelet aggregation in vivo is unknown but seems IVIg Infusions in ESRD Patients on Hemodialysis unlikely on the basis of published data. This is consistent with Administering IVIg is challenging in patients who are unable previous experiments in which IVIg did not cause an increase to tolerate high volumes or solute loads, such as those with in platelet ADP release and actually can reduce aggregation congestive heart failure and ESRD. This is particularly impor- that is seen with other agents (7,11). However, unless there is a tant for prekidney transplant recipients, who usually are dial- contraindication, we would recommend that patients who are ysis dependent and prone to volume overload. Like any other at higher risk for thrombosis or MI receive aspirin and hydra- blood product, we infused IVIg (Gamimune-N 10%) during tion (250 ml of 0.9 normal saline over 30 min) before IVIg hemodialysis and compared this with placebo (albumin 0.1%) infusion. There are no data to support any particular premed- as part of the NIH IG02 study (26). More than 300 infusions of ication regimen. However, our experience supports the pre- IVIg were given to 50 patients and compared with an equiva- IVIg infusion use of Benadryl 25 to 50 mg orally or intrave- lent number of placebo infusions to 52 patients. Analysis nously, Tylenol 650 mg orally, or aspirin 325 mg orally and showed that IVIg was well tolerated with a low incidence of Solu-Medrol 40 mg intravenously 30 min before the infusion to volume overload, pruritus, and rash. The number of minor reduce infusion-related adverse effects. Selection of products (7.7% in IVIg versus 7.5% in albumin) and significant (0.3% IVIg with lower osmolality or reduction in osmolality of sodium- lnJA o eho :8482 2006 844–852, 1: Nephrol Soc Am J Clin

Table 5. IVIg and renal failurea

Patient Total No. of Dose of Time Correlation between IVIg Infusion Comorbidities Indication for IVIg Rate of IVIg Infusion Age/Gender IVIg Doses IVIg and Onset of Symptoms

40/female S/p living-unrelated kidney transplant S/p kidney transplant ϫ 1 mo with 2 140 g over 8 h, 2.5 ml/kg per h Day 2: Follow-up at renal transplant with renal insufficiency (baseline positive cross-match clinic revealed that creatinine was creatinine 1.9) elevated from baseline of 1.9 to 2.3. Patient underwent biopsy, which showed early calcineurin toxicity. Renal function recovered after 4 d. 72/male S/p cadaveric kidney transplant with ITP 1 70 g over 6 h, 1.2 ml/kg per h Day 2: Creatinine increased from renal dysfunction (baseline creatinine baseline of 3.4 to 7.2. Patient required 3.4). Peripheral vascular disease hemodialysis. Renal function slowly recovered to better than baseline after 5 wk, and patient was taken off dialysis. 54/female Congestive heart failure with renal Positive QuickScreen PRA and cross- 2 70 g over 8 h, 1.2 ml/kg per h Day 2: Creatinine increased after second insufficiency, recent contrast dye match before heart transplant dose of IVIg from 1.3 to 1.9 with administration, gout anuria. Patient required hemodialysis and high-dose diuretic. Patient required dialysis for 1 wk but aeyadAvreEet fII o muoouain849 Immunomodulation for IVIg of Events Adverse and Safety recovered completely. 79/male Diabetes with CKD, baseline creatinine ITP 1 70 g 1.2 ml/kg per h Day 2: Creatinine increased from 1.3 to 1.5 to 2.2. Heart failure, gout, and 7.0. Patient became overtly uremic and nephrolithiasis. Atrial fibrillation required dialysis for 7 d. Renal function recovered and creatinine was back to baseline by 10 d after IVIg infusion. 70/female S/p cadaveric kidney transplant Positive cross-match before kidney 1 70 g over 4 h, 2.5 ml/kg per h Day 1: Delayed graft function transplant. Given right before immediately after kidney transplant. transplant Patient required hemodialysis for 1 wk but recovered completely. Biopsy showed proximal tubular cell vacuolization suggestive of IVIg- induced ATN. 39/female CKD secondary to cardiomyopathy with Positive QuickScreen PRA 1 75 g 1.2 ml/kg per h Day 2: Creatinine increased from 1.6 to baseline creatinine 1.6. Recent history 2.2 by day 3. Patient became overtly of prerenal azotemia from diuretic use uremic and required dialysis for 7 d. for management of CHF Renal function recovered and creatinine was back to baseline by 10 d after IVIg infusion. 850 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 1: 844–852, 2006 and Onset of Symptoms baseline of 0.9 to 1.4. Serumpeaked creatinine at 2.2 before falling tobaseline near of 1.0 after 2 wk.diuretics High-dose used to maintain urine output, but no dialysis was required baseline of 0.7 to 6.6. Patientdialysis required for 1 wk. Renal function recovered, and patient was off dialysis with baseline creatinine of 0.7 on discharge after 2 wk. Time Correlation between IVIg Infusion Day 2: Creatinine increased from

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

Rate of IVIg Infusion of osmotic injury by sucrose. The patient received a 12% solu- 0.5 ml/kg per h over 14 h, 1 ml/kg per h Day 1: Creatinine increased from tion. Shortly thereafter, the creatinine rose to 8 mg/dl, and the patient required dialysis. IVIg Dose of 40 g 140 g 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

IVIg Doses suggests that toxicity to proximal tubule cells as a result of a Total No. of 2 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. Fortu- nately, 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 Bullous pemphigoid 1 ITP 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 exces- sive volume and solutes such as sucrose and sodium, hemodi- Comorbidities Indication for IVIg alysis patients routinely are heparinized, which limits thrombotic complications. Therefore, we believe that the use of all hypercholesterolemia atrial fibrillation

Diabetes, peripheral vascular disease, 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 head-

Continued ache (52%), not unlike Carimune (50%) and Polygam (50%).

Patient Slowing the infusion rate and extending the administration 61/female 82/male Diabetes, peripheral vascular disease, Age/Gender CKD, chronic kidney disease; ATN, acute tubular necrosis.

a time to over 8 h significantly decreased the incidence of head-

Table 5. ache as well as other less severe adverse effects. Clin J Am Soc Nephrol 1: 844–852, 2006 Safety and Adverse Events of IVIg for Immunomodulation 851

Conclusion cases and review of the literature. Eur J Neurol 10: 367–372, It is important to understand that all IVIg products are not 2003 alike. They differ in salt and sugar content, pH, and osmolality. 10. Elkayam O, Paran D, Milo R, Davidovitz Y, Almoznino- Careful attention to the products that are provided by an insti- Sarafian D, Zeltser D, Yaron M, Caspi D: Acute myocardial infarction associated with high dose intravenous immuno- tution’s pharmacy is critical to avoid excipient-related adverse globulin infusion for autoimmune disorders. A study of effects. On the basis of our experience, all IVIg products can be four cases. Ann Rheum Dis 59: 77–80, 2000 administered safely if adverse effect profiles are recognized and 11. Gottlieb S: Intravenous immunoglobulin increases risk of appropriate patient selection and premedications are given. thrombotic events. BMJ 324: 1056, 2002 Because the use and indications for IVIg continue to expand 12. Hefer D, Jaloudi M: Thromboembolic events as an emerg- and higher doses and volumes are mandated for autoimmune ing adverse effect during high-dose intravenous immuno- and inflammatory disorders, it is critical to be aware of the globulin therapy in elderly patients: A case report and potential adverse effects that are associated with specific prod- discussion of the relevant literature. Ann Hematol 83: 661– ucts and, more important, how to prevent them. 665, 2004 13. Go RS, Call TG: Deep venous thrombosis of the arm after intravenous immunoglobulin infusion: Case report and Acknowledgments literature review of intravenous immunoglobulin-re- This work was supported by the Joyce Jillson Fund for Kidney lated thrombotic complications. Mayo Clin Proc 75: 83– Transplantation. S.C.J. is the recipient of research grant support from 85, 2000 Talecris Inc. and ZLB-Berhing, Inc. 14. 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