Intravenous immunoglobulin products (IVIG) are derived from pooled human plasma from thousands of donors and have been used for the treatment of primary immunodeficiency disorders for nearly 30 years. IVIG products are also effective in the treatment of autoimmune and inflammatory disorders, however the precise mechanism(s) of immune modulation are unknown. Recent data suggests that IVIG has a much broader ability to regulate cellular immunity, including innate and adaptive components. IVIG is also a recently recognized modifier of complement activation and injury. These attributes suggests IVIG would have clinical applications in solid organ transplantation. Analysis of clinical studies examining the use of IVIG in desensitization protocols and for treatment of antibody-mediated rejection (AMR) are supportive for kidney transplant recipients, although no clinical trials using IVIG in sensitized patients were performed seeking an Federal Drug Administration indication. Data regarding the use of IVIG for desensitization and treatment of AMR in cardiac and lung allograft recipients is not conclusive. IVIG is useful in the treatment and prevention of posttransplant infectious complications including cytomegalovirus, parvovirus B19 and polyoma BK virus. In addition, we address the risk of adverse events associated with IVIG use in sensitized end-stage renal disease and transplant patients.
Immunoglobulin molecules, B and T cells are the primary mediators of the adaptive immune system (1). Deficiency or absence of immunoglobulin molecules can occur as a result of congenital or acquired conditions that results in an increased predisposition for upper respiratory infections and susceptibility to autoimmune diseases (1,2). This counterintuitive relationship between immune deficiency and increased risk for autoimmune and inflammatory disorders suggest that immunoglobulin G (IgG) molecules may serve a dual role. First as mediators of sterilizing immunity, and as natural regulators of immunity and inflammation (1–3).
The remarkable story of intravenous immune globulin therapy (IVIG) began in 1980 with the introduction of the first suitable products for intravenous administration for patients with immune deficiencies (1–3). However, the antiinflammatory and immunomodulatory actions of IVIG were soon recognized with resultant applications to autoimmunity and systemic inflammatory conditions (4).
Licensed indications account for less than 50% of the current world wide usage, and the use of IVIG for an increasing number of conditions has more than doubled in the last decade (4). This raises a number of concerns regarding the rational application of IVIG therapy in autoimmune diseases and transplantation, especially where large controlled clinical trials cannot be performed (3).
IVIG has emerged as an important component of virtually all desensitization protocols and for treatment of antibody-mediated rejection (AMR). Dosing of IVIG is empiric and based on the clinical context. For example, IVIG is used at doses of ∼500 mg/kg monthly for hypogammaglobulinemia. However, the required dose for antiinflammatory effects, especially treatment of AMR is 1–2 gm/kg (1,3–8).
Although there are many excellent reviews (1,2–4) of the mechanism(s) of action of high dose IVIG and its applicability to the treatment of autoimmune diseases, this review will focus on analyzing data supporting clinical applications in solid organ transplant recipients.
Clinical Applications of IVIG in Kidney Transplant Recipients
The highly sensitized patient
Approximately 30% of end-stage renal disease (ESRD) patients awaiting transplantation are sensitized to HLA resulting from previous exposure through pregnancy, previous transplants, or blood transfusions (9).
Sensitization to HLA or ABO blood group antigens has emerged as a major barrier to kidney transplantation since transplantation across these immunologic barriers without proper modification results in a high rate of graft loss (8–10). These patients are greatly disadvantaged regarding candidacy for transplantation since wait times are more than double the national average (4 years PRA ≤10% vs. 8 years for PRA ≥10%). Approximately 80% of transplants performed in the United States are in nonsensitized patients, and this has not changed significantly over the past decade (9) (Figure 1A and B). Thus sensitized patients have extended wait times on dialysis with attendant comorbidities, increased mortality and cost.
Improving transplant rates in sensitized patients
Over the past decade, several centers have developed approaches to the sensitized patients that result in reduction of anti-HLA antibodies with improved rates of transplantation (8,10). These approaches have collectively been described as ‘desensitization’. Desensitization, in my opinion, is not the correct term since it refers to exposing a person to the object, item or experience they are sensitized to in order to gradually reduce levels of sensitization. With these considerations, a more appropriate terminology would be antibody reduction therapies and/or immunomodulation for transplantation.
Immunomodulation of sensitized patients is a high risk and highly specialized field of transplant medicine and immunology that is evolving rapidly. Development of immunomodulatory therapies requires careful monitoring of patients pre- and posttransplant to insure that risks for AMR and infectious complications are minimized. Without careful implementation of a coordinated team approach (transplant surgeons, nephrologist, HLA laboratory, plasmapheresis center, blood bank and renal pathology), the outcomes are likely to be suboptimal. There are currently no FDA approved drugs/protocols for immunomodulation of the sensitized patients, although there are numerous reports in the literature regarding approaches that might be construed as ‘best practices’, there is still no widespread agreement on management of the highly HLA sensitized patient. This issue was the topic of a recent FDA sponsored symposium aimed at developing consensus approaches for immunomodulation and treatment of AMR (http://www.fda.gov/Drugs/NewsEvents/ucm206132.htm).
Evidence for efficacy of IVIG as an immunomodulatory agent for highly HLA sensitized patients awaiting kidney transplantation
Here, we will focus on published peer reviewed data regarding the use of IVIG for immunomodulation of sensitized patients for transplantation. A recent paper by Shehata et al. (11) provided an extensive analysis of the published peer reviewed literature regarding IVIG use in solid organ transplantation. This is an excellent review and is recommended for detailed analysis of this topic. This work is an extensive analysis of the Canadian Blood Service and Canada's National Advisory Committee on Blood and Blood Products that represented a joint initiative to develop guidelines for IVIG use in the setting of solid organ transplantation. The committee reviewed 791 literature citations and 45 reports. The committee's recommendations were then reviewed by physicians involved in solid organ transplantation. Their efforts were aimed at developing evidence-based practice guidelines (11,12). A total of 19 studies were reported describing the use of IVIG for HLA incompatible and ABO incompatible kidney transplantation. Two were randomized controlled trials (8,13).
The committee recognized a number of limitations of their study, including the proper definition of sensitization, lack of standardization of HLA antibody testing platforms and the dosing and timing of IVIG therapy. However, they concluded the use of IVIG was associated with acceptable outcomes in this high risk group and was recommended for use in highly HLA sensitized ESRD patients to improve rates of transplantation.
For patients with a complement-dependent cytotoxicity (CDC +) crossmatch, the use of IVIG 2 gm/kg, monthly X4 (maximum dose 180 g/dose) and plasmapheresis (PP) + IVIG (100 mg/kg) given in the perioperative period were found to be equivalent therapies. For patients with a flow-cytometry positive crossmatch only, IVIG 2 gm/kg x1 or PP + IVIG (100 mg/kg) to achieve a negative or acceptable flow cytometry crossmatch were found to be equivalent (11,12).
Other studies not included in this review are also supportive. Mai et al. (14) reported on excellent allograft survival in donor-specific antibody (DSA) positive kidney transplant recipients using high-dose IVIG and antithymocyte globulin. Båchler et al. (15) recently reported on outcomes in DSA positive, crossmatch negative patients who were treated with IVIG and antithymocyte globulin. These patients were compared to a similar group of patients who were DSA positive but did not receive IVIG. During the first year, the IVIG + ATG group had fewer AMR episodes (11% vs. 46%) and better graft survival. 7.5% of allografts in the non-IVIG treated group failed from AMR in the first year versus 0% in the IVIG group. Thielke et al. (16) reported on the use of PP + IVIG for transplantation across a positive crossmatch in 57 candidates. All but six were transplanted with patient and graft survival at 1 year of 98%/93%, respectively. Magee et al. (17) described the use of PP + IVIG for immunomodulation of 29 patients with complement-dependent cytotoxicity (CDC)+ crossmatches. Twenty-eight of 29 were rendered crossmatch negative and were transplanted. At 22 months posttransplant, 89% of grafts are functional.
IVIG + Rituximab for immunomodulation of sensitized patients
We reported on a phase I/II trial investigating the safety and limited efficacy of adding rituximab to a modification of the high dose IVIG protocol (18). This protocol reduces the time of desensitization from 16 weeks to 5 weeks. The results of this trial showed a transplant rate of 80% for highly HLA sensitized patients studied (16/20). Rejection episodes occurred in 50% while patient and graft survival at 1 year were 100%/94%, respectively. Patients who received deceased donor transplants waited 144 ± 89 months (range, 60–324 months) on the transplant waitlist before receiving desensitization with IVIG and rituximab, but waited only 4.9 ± 5.9 months (range, 1.5–18 months) after treatment for a transplant. Our subsequent experience using a similar approach in 76 highly HLA sensitized patients confirms these observations. The AMR rate was 23% with patient and graft survival of 98% and 89% for both LD/DD recipients at 24 months posttransplant (19). The safety of this approach was also demonstrated in both studies.
More recently, Loupy et al. (20) performed a comparison of IVIG vs. IVIG + anti-CD20 + PP. They examined the immunologic, functional and histologic course of DSA positive patients who received DD transplants after either type of desensitization. In brief, no difference was seen in early AMR episodes. However, at 1 year there was a significant reduction in transplant glomerulopathy (7% vs. 38%, p = 0.02) on protocol biopsies for those receiving induction with IVIG + anti-CD20 and PP. In addition, the decline in DSA from baseline to 1 year was significantly greater in the IVIG + anti-CD20 +PE group (44 ± 13% vs. 80 ± 8%, p = 0.04). These authors conclude that the data support a long-term beneficial effect of the combined induction therapy in DSA positive patients receiving DD transplants.
Careful clinical trials will help resolve the role of rituximab as a desensitization agent.
Use of IVIG as a desensitization agent for heart and lung allograft recipients
Although IVIG high-dose treatment has been reported to be beneficial in the treatment of idiopathic and viral induced cardiomyopathies, support for its use in desensitization is less clear (11,21–23). Shehata et al. (11) recently summarized the experience using IVIG as a desensitization agent in patients undergoing cardiac transplantation and found that data was not supportive of its efficacy.
No randomized studies are reported and four reports did not define a response to treatment (11). No study showed that IVIG alone could reduce antibody and the results of survival after transplantation are conflicting. Despite this, desensitization is likely to be an important therapeutic intervention for transplant cardiologist. Controlled trials with desensitization agents where standardized biopsy grading systems and antibody analysis are used can answer this important question.
Apel et al. (24) found that using IVIG with antibody absorption columns in 12 patients did not reduce the rate of broncholitis obliterans syndrome (BOS) or increase survival in sensitized lung allograft recipients. More recently, a much larger and standardized study by Hachem et al. (25) was reported. These investigators examined the use of high dose IVIG and high dose IVIG + rituximab for treatment of lung transplant recipients who developed DSA posttransplant. Among 116 patients screened, 65 developed DSA posttransplant and were treated with high dose IVIG alone or IVIG + rituximab. Patients who failed to clear their DSA had significantly poorer survival at 3 years posttransplant. Among those who cleared DSA, the combination of IVIG + rituximab was superior to treatment with IVIG alone.
IVIG for treatment of AMR
We and others described the benefits of high-dose IVIG in treating resistant AMR episodes (5–7). Shehata et al. (11) recently reported on an evidence-based analysis of IVIG usage in treatment of AMR. The authors conclude that there is sufficient evidence to support the use of IVIG for treatment of ARM. However, there is not enough evidence to conclude that IVIG alone is sufficient to treat AMR without addition of concomitant PP. Lefaucher et al. (26) recently reported on a retrospective comparison of high-dose IVIG alone (12 patients) versus IVIG + rituximab + PP (12 patients) for treatment of AMR. The investigators found that the combined therapy was superior to IVIG alone in providing improved graft survival at 36 months (91.7% combined vs. 50% IVIG alone, p = 0.02) and providing long-term suppression of DSA levels.
Recently, our group evaluated 172 highly HLA sensitized patients transplanted after desensitization (7/06–12/09). Thirty- eight patients developed AMR posttransplant, usually within the first month. All were treated with a combination of steroids (10 mg/kg daily × 3), IVIG 2 gm/kg (maximum dose 140 g × 1), and rituximab (375 mg/m2× 1). Some patients also received PP and two underwent splenectomy. Ten of the 38 patients lost their allograft to severe AMR (27).
Kaposztas et al. reported 2-year outcomes in their recent retrospective study looking at 54 patients treated for AMR (28). Group A had 26 patients that underwent treatment with PP + IVIG and rituximab and Group B had 28 patients who received PP + IVIG without rituximab. Two-year graft survival was significantly better in the group that received rituximab (90% vs. 60%) with the difference attributed to rituximab. Kessler et al. (29) recently reported the complete reversal of an AMR episode and DSA in an islet transplant using the combination of IVIG + rituximab.
Current treatment of AMR probably requires a combination of rituximab with PP and low-dose IVIG or high-dose IVIG (1–2 gm/kg) + rituximab.
Use of IVIG in treatment of secondary hypogammaglobulinemia and infectious complications in solid organ transplant recipients
Hypogammaglobulinemia usually results from common variable immunodeficiency syndrome and is also referred to as primary immunodeficiency (PID). As previously mentioned, PID is characterized by recurrent bouts of upper respiratory tract infections, gastrointestinal infections and a proclivity for autoimmune or allergic diseases (2,30). Normal IgG levels range from 700 to 1600 mg/dL, but clinically significant deficiencies can be seen below 500 mg/dL. In addition, it is important to realize that subclass (IgG1–IgG4) and IgA deficiencies can occur with normal levels of total IgG. This should always be part of the evaluation.
The use of potent immunosuppressive agents in solid organ transplant recipients may predispose individuals to development of secondary immunodeficiency with hypogammaglobulinemia. The clinical and laboratory manifestations are similar to those described for PID. Mawhorter and Yamani (30) recently reported on hypogammaglobulinemia and risk for infections in solid organ transplant recipients. They found that the risk for hypogammaglobulinemia is significant with long-term immunosuppression. This commonly manifest as recurrent fungal and viral infections that are resistant to standard antifungal and antiviral agents. A significant reduction of risk for infection was seen if IVIG replacement therapy (500 mg/kg, monthly) or CMV hyperimmune globulin (150 mg/kg, monthly) was given.
IVIG may also have utility in treating resistant CMV infections and BK nephropathy (31,32). We and others have reported the benefits of IVIG therapy in the treatment of chronic parvovirus B19 infections (PVB19) posttransplant. This includes the treatment of PVB19 induced pure red cell aplasia and collapsing glomerulopathy variant of focal glomerulosclerosis (33,34). We have described persistent CMV infection in posttransplant kidney and bone marrow recipients that failed to clear with high-dose ganciclovir therapy. These patients also had a demonstrated defect in development of CMV-specific cytotoxic CD8+ T-cells. Passive immunity with CMV-specific IgG resolved CMV viremia and disease in these patients (32). Potena et al. reported on the efficacy of CMV-specific IgG and ganciclovir in clearing CMV viremia and prevention of allograft vasculopathy postheart transplant (35).
Posttransplant patients should be monitored for hypogammaglobulinemia using total IgG and subclass measurements (IgG1–IgG4) especially if there is a history of recurrent infections. Monthly IVIG replacement is effective in correcting this immunedeficiency (11,12).
Complications of IVIG therapy
Unlike the use of IVIG in immunodeficiency, patients who are highly HLA sensitized require higher doses (1–2 g/kg/dose) to achieve a beneficial outcome. The use of higher doses and concentrations of IVIG products results in higher rates of infusion-related complications. These can include aseptic meningitis, thrombotic events and bronchospasms. We have reviewed the complications associated with IVIG infusions in patients with normal renal function and those on dialysis (8,36). In brief, the safety of IVIG infusions (2 g/kg) doses given over a 4-h hemodialysis session, monthly × 4 versus placebo (0.1% albumin) in equivalent doses was studied in the IG02 trial (8). Adverse events were similar in both arms of the study (24 IVIG vs. 23 placebo). The most common adverse event in the IVIG arm was headache (52% vs. 24%, p = 0.056). Thus we concluded from this double-blind placebo-controlled trial that high-dose IVIG infusions during hemodialysis are safe.
A retrospective analysis of infusion-related adverse events associated with various IVIG products found that adverse events could be related to differences in excipient content and osmolality (36). In brief, lyophilized products that were reconstituted in normal saline often exhibited osmolalities >700 mOsm/L. Significant adverse events seen with high dose infusions included thrombotic events (Polygam®) and acute renal failure with sucrose containing products. These are briefly reviewed in Table 1. IVIG products have evolved and currently most products on the US and Canadian markets are liquid, isosmolar products that have extensive screening and treatments to remove the possibility of transmission of any type of pathogen. The composition of these products may affect their tolerability profile (Table 1), but these modifications have increased the safety, tolerability and efficacy of pooled IVIG products, with one exception.
Table 1. Characteristic affecting tolerability and side effects of various IVIG products
2Kahwaji et al. Clin J Am Sec Nephrol 4:1993–1997, 2009.
3%, 6%, 9%, 12%
5% or 10%
Sucrose, 1.67 g per gram of protein
D-Sorbitol, 50 mg/mL
Glucose, 20 mg/mL (5% concentration)
Maltose, 100 mg/mL
<20 mg per gram of protein
< 3.2 mEq/L (< 0.02%)
≤ 30 mmol/L
mOsm/kg: In sterile water: 576 (9%), 768 (12%) In 0.9% NaCI: 882(9%), 1074 (12%) In 5% dextrose: 828 (9%), 1020 (12%)
5% 636 mOsm/L 10% 1250 mOsm/L
6.8 ± 0.4 (5% concentration)
Reported adverse events
IVIG and hemolytic anemia
Chromatographically derived IVIG products contain antiblood group antibodies (i.e. anti-A/B) in higher titers than seen with lyophilized preparations (37). Titers of anti-A vary from different IVIG products, with the liquid, isosmolar products having the highest titers and more likely associated with episodes of clinical hemolysis (Table 2).
Table 2. Antiblood group (anti-A/B) titers in various IVIG products
1Denotes liquid, isosmolar IVIG products prepared by chromatography techniques where hemolysis can be seen.
We recently reported a series of 18 cases of IVIG induced hemolytic anemia in highly HLA sensitized patients, following IVIG infusions on dialysis. All patients had a positive direct antiglobulin test. Average pre- and post-IVIG hemoglobin values were 11.6 and 7.8 g/dL. Eighty-three percent of patients required blood transfusions. All cases of hemolysis were observed in patients that received liquid preparations of IVIG (Gamunex 10%, Gammagard® Liquid 10% and Privigen® 10%). Patients who are blood group A, B or AB receiving high-dose IVIG should be monitored for development of hemolytic anemia.
The therapeutic diversity of IVIG ranges from providing sterilizing immunity from infections to functionally efficacious modulation of immunity. These attributes are unique and for these reasons suggest IVIG will likely have an important role in clinical transplantation for many years to come.
Over the next 5 years, IVIG usage in transplantation is likely to increase dramatically. This relates to its efficacy in desensitization protocols, preventing and treating infectious complications and treatment of AMR. Although no drugs are yet FDA approved for treatment of AMR or desensitization, IVIG has the most supportive data (11,12) and is recommended as best ‘standard practice’ for these reasons. Other important issues include continuing basic research into mechanisms of action that are relevant to transplant medicine and identification or modification of IVIG products to deliver a more powerful immunomodulatory signal. The use of IVIG alone or in combination with other complement modifiers will be an important step forward in the prevention and treatment of AMR.
The Rebecca Sakai Memorial Fund and the Joyce Jillson Fund for Transplant Research. We also want to express our gratitude to the entire staff of the Transplant Immunotherapy Program at Cedars-Sinai Medical Center for their hard work and dedication.
The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Drs. Toyoda, Kahwaji and Vo have no conflict of interest to declare. Dr. Jordan owns a patent: US Patent 6,171,585B1, ‘IVIG Immunosuppression in HLA Sensitized Transplant Recipients’ (Submitted 1994, Awarded 2001). Dr. Jordan also receives grant support from Genentech Inc.