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Intravenous Immunoglobulin and Plasmapheresis in Acute Humoral Rejection

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  • 1. Intravenous Immunoglobulin and Plasmapheresis in Acute Humoral Rejection: Experience in Renal Allograft Transplantation Ruediger W. Lehrich, Paulo N. Rocha, Nancy Reinsmoen, Arthur Greenberg, David W. Butterly, David N. Howell, and Stephen R. Smith ABSTRACT: Acute humoral rejection (AHR) in kidney transplantation is associated with higher rates of allograft loss when compared with acute cellular rejection (ACR). Treatment with intravenous immunoglobulin (IVIG) combined with plasmapheresis (PP) has been used re- cently in many centers. We report the incidence, clinical characteristics, and outcome of patients with AHR treated with IVIG and PP. All patients (n ϭ 519) at our insti- tution who underwent kidney transplantation between January 1999 and August 2003 were retrospectively an- alyzed and classified according to biopsy results into three groups: AHR, ACR, and no rejection. AHR was diag- nosed in 23 patients (4.5%) and ACR in 75 patients (15%). Mean follow-up was 844 Ϯ 23 days. Female sex, black race, and high panel-reactive antibody were risk factors for AHR. Most AHR patients (22 of 23) were treated with IVIG and PP. Two-year graft survival was numerically worse in patients with AHR versus ACR (78% vs. 85%, p ϭ 0.5) but the difference was not statistically significant. Graft survival after AHR treated with IVIG and PP is much better than it has been historically. IVIG in combination with PP is an effective treatment for AHR. Graft survival in this setting is similar to graft survival in patients with ACR. Human Immunology 66, 350–358 (2005). © American Society for Histocompatibility and Immunogenetics, 2005. Pub- lished by Elsevier Inc. KEYWORDS: renal allografts; acute humoral rejection; intravenous immunoglobulin; plasmapheresis; allograft survival ABBREVIATIONS ACR acute cellular rejection AHR acute humoral rejection CDC-AHG complement-dependent cytotoxicity technique enhanced with antihuman globulin IVIG intravenous immunoglobulin No REJ no rejection PP plasmapheresis PRA panel-reactive antibody INTRODUCTION Acute humoral rejection (AHR) occurs early, usually within 24 to 48 hours after reperfusion. Characteristic pathologic features include severe injury to endothelial cells lining small blood vessels, inflammatory infiltrates, and intravascular coagulation [1]. Antidonor antibodies are involved in its pathogenesis [2, 3]. Saadi et al. [4] hypothesized that binding of antidonor antibodies to vascular endothelial cells in concert with activation of From the Duke University Medical Center, Department of Medicine, Division of Nephrology, Durham, NC, USA (R.W.L., D.W.B., A.G., S.R.S.); Federal University of Bahia, Department of Medicine, Salvador, BA, Brazil (P.N.R.); and Duke University Medical Center, Department of Pathology, Durham, NC, USA (N.R., D.N.H.). Address reprint requests to: Dr. Ruediger W. Lehrich, Duke University Medical Center, Department of Medicine, Division of Nephrology, PO Box 3014, Trent Drive, Durham, NC 27710; Tel: (919) 660-6857; Fax: (910) 684-4476; E-mail: Lehri001@mc.duke.edu. R.W.L. and P.N.R. contributed equally to this study. Received December 15, 2004; accepted January 19, 2005. Human Immunology 66, 350–358 (2005) © American Society for Histocompatibility and Immunogenetics, 2005 0198-8859/05/$–see front matter Published by Elsevier Inc. doi:10.1016/j.humimm.2005.01.028
  • 2. complement leads to a process that he termed the “acti- vation” of endothelium. The endothelium is rendered permeable, allowing penetration of immunocompetent cells, leading to the characteristic picture of inflamma- tion, thrombosis and ischemia [5]. AHR is less fre- quently encountered than acute cellular rejection (ACR). The latter responds well to therapy directed against T lymphocytes as a preventive and therapeutic strategy [6]. AHR is relatively unresponsive to therapies that target T lymphocytes. Treatment focuses rather on removal of preformed alloantibodies against donor-specific human leukocyte antigens (HLA). This can be accomplished by means of plasmapheresis (PP) in combination with im- munosuppressive agents that inhibit B-cell proliferation, such as mycophenolate. In renal transplantation, AHR has a poor prognosis for immediate graft survival [6]. Grafts that do survive are subject to impaired long-term allograft function, and patients experience early allograft loss [3, 7]. Reports that used conventional therapy reveal that 1-year graft survival does not exceed 15%–50% [8, 9]. New treat- ment strategies that use intravenous immunoglobulin (IVIG) have been found to be more efficacious. Several studies, including a recently published report by our group [10–13], describe the combined use of PP or other means of immunoadsorption in conjunction with IVIG and standard maintenance immunosuppression. IVIG has immunomodulatory properties and is effec- tive in treating several autoimmune and inflammatory conditions such as immune thrombocytopenic purpura, hemolytic anemias, and autoimmune neutropenias [14]. Various actions of IVIG have specific relevance to alloan- tibody-mediated acute rejection of transplanted allo- grafts. These include neutralization of autoantibodies [15], inhibition of activation of endothelial cells [16], downregulation of antibody synthesis as a result of inhi- bition of B- and T-cell proliferation [17–19], and in- creased apoptosis of B cells [20]. These properties of IVIG may explain its role as a helpful adjunct in the treatment of AHR. In our experience with AHR in renal allografts, the combined use of IVIG and PP is associated with a 1-year graft survival of 81% [10]. In the current study we describe the extension of that experience by expanding the study group and follow-up. We now describe 23 patients with AHR who were treated with PP and IVIG, and we report outcome data extending more than 2 years. MATERIALS AND METHODS Study Group Our study group consisted of all consecutive kidney or kidney-pancreas transplants performed at Duke Univer- sity Medical Center between January 1999 and August 2003 (n ϭ 519). Data collection consisted of a review of medical records. We had a preexisting database contain- ing demographic and clinical information on all patients transplanted between January 1999 and August 2001; data for patients transplanted between August 2001 and August 2003 were added to this database. Follow-up for all patients was extended to August 2004. Pathology and Immunopathology Biopsies were performed to evaluate allograft dysfunc- tion; protocol biopsies were not performed. Biopsy re- sults were used to classify patients into rejection groups, namely ACR or AHR. Patients with no biopsy-proven evidence of rejection or who did not undergo biopsy were assigned to the no rejection group (No REJ). Transplant biopsy samples were routinely processed and stained by hematoxylin-eosin, periodic acid–Schiff, methenamine silver, and Masson trichrome methods. ACR was diag- nosed and graded according to the Banff 1997 criteria [21]. The diagnosis of AHR was suggested by the fol- lowing histologic criteria: interstitial infiltrate of inflam- matory cells (1) involving more than 25% of biopsy tissue, (2) with predominant focus on peritubular capil- laries, (3) composed at least in part of neutrophils, and (4) associated with minimal tubulitis. AHR was con- firmed on the basis of criteria recently published by the Banff group [22]. Patients who had biopsy-proven typ- ical histology for AHR and who had either positive staining for C4d or presence of donor-specific HLA an- tibodies were considered to have confirmed AHR. C4d staining was performed on a frozen section by means of a mouse monoclonal anti-C4d antibody (Biogenesis, San- down, NH). Renal transplant biopsy samples after Feb- ruary 2001 were routinely stained with anti-C4d anti- body. Stored frozen tissue from biopsies performed between January 1999 and February 2001 were retro- spectively stained for C4d. At the time of initial workup, sera from all kidney transplant candidates were evaluated for the presence of anti-HLA immunoglobulin (Ig) G antibodies by means of both the complement-dependent cytotoxicity tech- nique enhanced with antihuman globulin (CDC-AHG) and flow cytometry techniques (flow panel-reactive an- tibody [PRA]) [23]. The CDC-AHG technique for T- cell panel analysis and the complement dependent cyto- toxicity (CDC) (NIH modified, three wash) technique for B-cell panel analysis were used to determine whether any antibody detected had cytotoxic properties or whether any IgM was present. Dithiothreitol was used to reduce any IgM present, thereby allowing for the detection of IgG antibodies by the cytotoxic techniques. Because flow cytometry is three times more sensitive than the CDC- AHG technique, it was used to determine the presence of 351IVIG and Plasmapheresis in Humoral Rejection
  • 3. any HLA-directed antibody. Also, the flow cytometry technique can specifically identify HLA class I– versus class II–directed IgG antibodies. The fine specificity of any antibody detected was analyzed by flow cytometry by means of specificity beads, latex beads coated with class I or class II HLA molecules, as well as single antigen beads and latex beads coated with molecules of a single HLA class I or class II allele (One Lambda, Canoga Park, CA). In this manner, the exact specificity of the antibody can be determined to identify alleles in the donor population that would be unacceptable antigens. The final cross match included a CDC-AHG T-cell and CDC (three wash) B-cell cross match for all donor- recipient combinations, and a flow cytometry T- and B-cell cross match for all recipients with HLA-directed antibodies detected by flow cytometry. PRAs before transplantation were obtained on all patients. CDC-AHG, enzyme-linked immunosorbent as- say, and flow cytometry techniques were used, and peak historic PRAs were recorded for the purpose of this study. If flow cytometry PRAs were available (they were routinely used starting in January 2000), they were reported. If flow cytometry PRAs were not available, enzyme-linked immunosorbent assay or CDC-AHG PRAs were reported. Flow cytometry PRAs were avail- able in the majority of patients. For simplicity of pre- sentation, the results are presented as T- and B-cell PRAs, regardless of the method used. Patient Characteristics, Treatment, and Outcome Charts were screened for demographic patient character- istics, namely sex, race, age, and type of transplant (liv- ing donor or deceased donor). Furthermore, the following transplant-specific data were extracted: cold ischemia time, presence of delayed graft function (defined as the need for renal replacement therapy in the first week after transplantation), type of induction therapy (daclizumab or antithymocyte globulin), historic peak T- and B-cell PRA, and modality of treatment (PP and IVIG, PP alone, IVIG alone, pulse methylprednisolone, antithy- mocyte globulin, and muromonab-CD3). Maintenance immunosuppression in all patients con- sisted of a calcineurin inhibitor (tacrolimus or cyclospor- ine), mycophenolate, and prednisone. Patients who were identified as having AHR received a combined regimen of PP and IVIG (Gamimune, Bayer Biological Products, Research Triangle Park, NC; or Venoglobulin, Alpha Therapeutic, Los Angeles, CA). A typical PP regimen consisted of four daily sessions (range 3–6 days) with 5% human albumin replacement. The number of PP sessions was based on the clinical response to therapy as measured by urine output and serum creatinine. IVIG, usually at a dose of 2 g/kg, was administered after the last PP session. However, there was a wide dose variation. The primary outcome measure was return to renal replacement therapy after kidney transplantation. Sec- ondary outcome measures were last serum creatinine at end of follow-up and patient survival. Statistical Analysis The results were summarized as mean Ϯ SEM or median and interquartile range. Continuous variables were com- pared by the two-tailed unpaired t-test, and dichotomous variables were compared using 2 ϫ 2 contingency tables and Fischer’s exact test. Survival analysis was performed with the Kaplan-Meier method, and comparisons be- tween survival curves were made by the log-rank test. Statistical significance was defined as a p value of less than 0.05. All data analysis was performed by SAS Sys- tem for Windows, version 8, and SAS Enterprise Guide (SAS Institute, Cary, NC). RESULTS Between January 1999 and August 2003, a total of 519 patients underwent a kidney or combined kidney-pancreas transplantation at our institution. Mean follow-up was 884 Ϯ 23 days. Seventy-five patients had at least one episode of ACR. On the basis of light microscopic findings, 29 patients had AHR. The re- cently developed consensus criteria for the diagnosis of AHR were then used to confirm AHR [22]. This en- tailed C4d staining of frozen sections of transplant biopsy samples and screening for donor-specific HLA antibod- ies. C4d staining was performed on all 29 biopsy sam- ples, and donor-specific HLA antibody screening was performed on 23 (79%) of 29 patients. In 13 of 29 patients, donor-specific HLA antibody screening was performed at the time of rejection. In 10 of 29 patients, donor-specific HLA antibody screening was performed at the time of transplantation. We defined AHR as pres- ence of typical findings on light microscopy and presence of either C4d staining or presence of donor-specific an- tibodies. With this stringent approach, we were able to confirm AHR in 23 patients and excluded the remaining 6 patients from the analysis (Figure 1). The baseline characteristics of patients who developed ACR, AHR, or No REJ are summarized in Table 1. Although most demographic values did not differ be- tween the groups, patients who experienced AHR were significantly more likely to be black and female (AHR vs. No REJ: p ϭ 0.0161 and p ϭ 0.0003, respectively). Age and donor source were similar among groups. Table 2 lists the clinical characteristics of our cohort. Cold ischemia time was similar in all three groups. Patients who developed AHR were significantly more 352 R.W. Lehrich et al.
  • 4. likely to have had delayed graft function (AHR vs. No REJ: p ϭ 0.0005). Use of induction therapy was similar in all three groups. The time to rejection was defined as the interval between renal transplantation and the diag- nostic biopsy. Not surprisingly, AHR was diagnosed earlier than ACR (median at day 6 vs. day 70, p ϭ 0.0071). However, two patients were found to have AHR late in their transplant course, at days 147 and 843. Precipitating factors were unclear in the first pa- tient but medication noncompliance was found to be the cause in the second patient. All other patients in the AHR group (21 of 23) experienced rejection between days 3 and 14. Patients in the AHR group had a significantly higher mean T- and B-cell PRA compared with patients in the ACR or No REJ group (mean B-cell PRA: AHR vs. No REJ and ACR: p ϭ 0.0001 and p ϭ 0.0001, respectively; mean T-cell PRA: AHR vs. No REJ and ACR: p ϭ 0.0001 and p ϭ 0.0002, respectively). When historic peak PRAs were categorized as negative (Ͻ10%), moderate (Ͼ10%–Ͻ50%), or high (Ͼ50%), we observed a bimodal distribution of peak PRAs in the AHR group. Negative B- and T-cell PRAs were found in 47.8% and 47.9% of patients with AHR, respectively. High B- and T-cell PRAs were identified in 43.5% and 47.9%, respectively. The majority of patients in the ACR and No REJ group were found to have a negative PRA (Figure 2). The treatment of AHR consisted of PP and IVIG in almost all patients (22 of 23). One patient received PP alone. Eleven patients additionally received pulse meth- ylprednisolone therapy, and seven patients received ei- ther Thymoglobulin or OKT3 (Table 2). Most (20 of 23) patients responded to therapy with improved renal func- tion. Of the nonresponders, one patient required hemo- dialysis on postoperative day 1 and underwent transplant biopsy on day 6, the findings of which revealed AHR. The patient was treated with methylprednisolone at that point. PP and IVIG were initiated after a second biopsy was performed on day 12, which revealed persistent AHR. AHR could not be reversed, and the patient continued to need renal replacement therapy. Transplant nephrectomy was performed 7 months after the trans- plant. The second patient was diagnosed on postopera- tive day 2 with AHR and was treated with PP and IVIG starting on day 3. The patient was discharged requiring hemodialysis and died on postoperative day 30. The TABLE 1 Demographic characteristics of patients who underwent renal transplantation with and without acute rejection Characteristic All (n ϭ 513) AHR (n ϭ 23) ACR (n ϭ 75) No REJ (n ϭ 415) Age (years), mean Ϯ SD 46 Ϯ 0.6 45 Ϯ 2.6 42 Ϯ 1.5 47 Ϯ 0.6 Sex, n (%) Male 302 (59%) 5 (22%) 45 (60%) 252 (61%) Female 211 (41%) 18 (78%)a 30 (40%) 163 (39%) Race, n (%) White 292 (57%) 8 (35%) 31 (41%) 253 (61%) Black 214 (42%) 15 (65%)b 44 (59%) 155 (37%) Other 7 (1%) 0 0 7 (2%) Type of transplant, n (%) Living donor 197 (38%) 8 (35%) 24 (32%) 165 (40%) Cadaveric transplant 316 (62%) 15 (65%) 51 (68%) 250 (60%) a p ϭ 0.0003 vs. No REJ. b p ϭ 0.0161 vs. No REJ. FIGURE 1 Retrospective analysis of all consecutive kidney and kidney-pancreas transplants performed at Duke University Medical Center between January 1999 and August 2003. Follow-up was extended until August 2004. 353IVIG and Plasmapheresis in Humoral Rejection
  • 5. third patient was found to have AHR on postoperative day 7; therapy with PP and IVIG was immediately initiated. Subsequently, this patient developed systemic inflammatory response with acute respiratory distress syndrome, which was thought to be related to the epi- sode of acute rejection. A transplant nephrectomy was performed on postoperative day 13. In the No REJ group, cumulative 2-year graft survival was 94%, which was significantly higher than in both rejection groups (ACR vs. No REJ: p Ͻ 0.0001; AHR vs. No REJ: p ϭ 0.0002). Patients with ACR and AHR had 2-year graft survival of 85% and 78%, respectively (Figure 3). There was no significant difference in 2-year graft survival between rejection groups (ACR vs. AHR: p ϭ 0.50). Regarding patient survival, there was a sig- nificant difference between patients in the ACR group and No REJ (2-year patient survival: ACR 95% vs. No REJ 98%, p ϭ 0.013). There were two deaths in the AHR group (2-year patient survival: AHR 95%), but mortality difference between the AHR group and No REJ did not reach statistical significance (AHR vs. No REJ: p ϭ 0.09) (Figure 4).. Last follow-up mean serum creatinine of patients with functioning allografts for the AHR, ACR, and No REJ groups were 1.8 mg/dl, 1.5 mg/dl, and 1.6 mg/dl, respectively (Table 3). DISCUSSION We report the results of a single-center retrospective analysis of incidence and outcome of AHR in renal transplantation. The central findings of this study are as follows: (1) AHR occurs with an incidence of 4.4%, affects predominantly highly sensitized patients, and is observed early in the transplant course; (2) the combina- tion of IVIG and PP is an effective strategy for the treatment of AHR; and (3) 2-year graft survival of AHR with this regimen is better than in historic controls and comparable to graft survival in ACR. When AHR was defined as allograft dysfunction with typical light microscopic findings, as well as the presence of positive C4d staining or of donor-specific antibodies, the incidence of AHR in our study is comparable to previous assessments of incidence and falls well into the described range of 3%–10% [7, 24, 25]. The use of evaluating allograft dysfunction for AHR with a com- bined approach consisting of light microscopic evalua- tion, immunofluorescence staining for C4d, and screen- ing for donor-specific antibodies is now well established and has been validated in several retrospective cohort studies [7, 22, 24, 25]. We think that this approach TABLE 2 Clinical characteristics of patients who underwent renal transplantation Characteristic AHR (n ϭ 23) ACR (n ϭ 75) No REJ (n ϭ 415) Transplant characteristics Cold ischemia time, mean Ϯ SD 11.7 Ϯ 2.5 20.2 Ϯ 1.1 18.8 Ϯ 0.7 Delayed graft function, n (%) 13 (56%)a 19 (25%) 90 (22%) Induction therapy, n (%) 17 (74%) 43 (57%) 241 (58%) Peak B-cell PRA, mean Ϯ SD 39%bc Ϯ 8.7% 7% Ϯ 2.5% 6% Ϯ 1.0% Peak T-cell PRA 43%de Ϯ 8.9% 9% Ϯ 2.9% 8% Ϯ 1.1% Time to rejection, median (IQR) 6f (5–8) 70 (7–356) NA Therapy for rejection, n (%) PP ϩ IVIG 22 (96%) 0 NA PP alone 1 (4%) 0 NA IVIG alone 0 0 NA Pulse methylprednisolone 13 (57%) 37 (49%) NA Thymoglobulin or OKT3 7 (30%) 38 (51%)g NA a p ϭ 0.0005 AHR vs. No REJ. b p ϭ 0.0001 ACR vs. No REJ. c p ϭ 0.0001 AHR vs. ACR. d p ϭ 0.0001 AHR vs. No REJ. e p ϭ 0.0001 AHR vs. ACR. f p ϭ 0.0071 AHR vs. ACR. g In combination with pulse methylprednisolone in patients with ACR. Cold ischemia time (hours); time to rejection (days). 354 R.W. Lehrich et al.
  • 6. allowed us to reliably identify all patients with AHR to retrospectively study the effectiveness of therapy with IVIG and PP in AHR. Patients in the AHR group had clinical features sim- ilar to those previously described in patients with acute alloantibody-mediated rejection. It is well established that AHR occurs early in the transplant course, with a median onset after transplantation measuring days rather than weeks [7]. The median onset of AHR in our study was 6 days, with 50% of patients developing AHR between days 5 and 8 after transplantation. However, we were able to identify one patient who developed AHR FIGURE 2 PRA frequencies according to PRA intensity. Solid bars ϭ B-cell PRAs; open bars ϭ T-cell PRAs. PRAs Ͻ10% were considered negative; PRAs 10%–50% were con- sidered moderately elevated; and PRAs Ͼ50% were consid- ered high. There were significantly more patients with high PRAs in the AHR group compared with the ACR or the No REJ group. *B-cell PRA: AHR vs. ACR and No REJ: p ϭ 0.0001 and p ϭ 0.0001, respectively. **T-cell PRA: AHR vs. No REJ and ACR: p ϭ 0.0001 and p ϭ 0.0001, respectively. FIGURE 3 Kaplan-Meier allograft survival curves with groups as follows: No REJ group (solid line), ACR group (dashed line), and AHR group (dotted line). Numbers above x-axis at months 0, 6, 12, 18, 24, 30, and 36 represent number of patients after censoring event. Cumulative graft survival was significantly better in the No REJ group compared with ACR and AHR (ACR vs. No REJ: pϽ 0.0001; AHR vs. No REJ: p ϭ 0.0002). Graft survival between the AHR and ACR groups was not significantly different (p ϭ 0.50). FIGURE 4 Kaplan-Meier patient survival curves with groups as follows: No REJ group (solid line), ACR group (dashed line), and AHR group (dotted line). Numbers above x-axis at months 0, 6, 12, 18, 24, 30, and 36 represent number of patients after censoring event. Cumulative patient survival was significantly better in the No REJ group compared with ACR (ACR vs. No REJ: p ϭ 0.013). AHR patient survival was not statistically different when compared with the ACR or the No REJ group. 355IVIG and Plasmapheresis in Humoral Rejection
  • 7. precipitated by medication noncompliance more than 2 years after transplantation. It is conceivable that sup- pressed memory B cells were reactivated when immuno- suppression was suboptimal, leading to late acute alloantibody-mediated rejection. Highly sensitized pa- tients are more likely to develop AHR [3, 7, 26]. Women in our cohort were significantly more likely to develop AHR. This may relate to the higher rate of sensitization observed in women as a result of previous pregnancies. Last, elevated PRAs are markers of sensiti- zation. It is therefore not surprising that patients in the AHR group had significantly elevated historic peak PRAs. However, PRA distribution was bimodal, and roughly half of patients in the AHR group had a negative PRA. Thus, a detectable PRA does not identify all patients at risk for AHR. This emphasizes the notion that donor-specific antibodies other than HLA antibod- ies, and nonclassical HLA antibodies that are not de- tected by the PRA method might play a role in AHR. In cardiac transplantation, antiendothelial antibodies have been demonstrated to be associated with acute humoral but not ACR [27]. In renal transplantation, antibodies to MHC class I–related A antigen were found to be corre- lated with rejection and early graft loss [28]. The pres- ence of activating antibodies to angiotensin II type 1 receptors was associated with steroid resistant rejec- tion in a cohort of kidney transplant recipients who also had malignant hypertension [29]. IVIG in combination with PP has been used by us and others to treat AHR [10–13]. The commercial prepara- tions of IVIG used in clinical practice contain intact IgG molecules with a distribution of subclasses closely resem- bling that in the human serum. IVIG represents pooled plasma from approximately 3000–10,000 healthy do- nors [14]. A body of experimental and clinical evidence suggests various potential actions of IVIG that might explain its usefulness in treating AHR. In patients with autoimmune hemophilia, IVIG has been demonstrated to neutralize autoantibodies [15]. This is likely because of a high concentration of antiidiotypic antibodies in IVIG directed against autoantibodies. In experimental models of inflammatory activation of endothelial cells, IVIG has been demonstrated to inhibit tumor necrosis factor ␣– and interleukin 1␤–induced gene transcription of adhesion molecules and cytokines [16, 29]. IVIG likely behaves as normal IgG and IgM regarding the control of autoreactivity of antibodies in human plasma [30]. Normal IgG and IgM function includes the sup- pression of migration of B-cell populations from the bone marrow to secondary lymphoid organs, as found in mice [31]. Furthermore, IVIG has been demonstrated to downregulate specific autoreactive B-cell populations in animal models of inherited immunodeficiency [32]. It can therefore be speculated that IVIG might have prop- erties that are helpful in decreasing donor-specific anti- body load and reducing harmful B-cell populations in patients with AHR. In our study, treatment of AHR with PP and IVIG is associated with 2-year graft survival of 78%. Therapy with PP alone is associated with inferior results [24, 33], likely because of early rebound of alloantibodies. Historic controls indicate that the graft loss without specific therapy is 15%–50% [8, 9]. In our experience IVIG and PP are helpful modalities to treat AHR, but our study and similar studies by other groups must be interpreted with caution. All conducted studies are retrospective. Despite our encouraging results, graft loss in AHR re- mains higher than in transplant recipients without re- jection. New strategies involving alternative treatment modalities are being investigated. Thymoglobulin in combination with PP was recently used to treat renal transplant patients with AHR. In a small, uncontrolled study, no difference in graft survival between the AHR group and the no rejection group was observed, making this a promising treatment modality [34]. Rituximab, a genetically engineered chimeric human-murine anti– CD-20 monoclonal antibody, has been used to treat AHR. This approach appears reasonable because CD-20 is involved in the regulation of B-cell development and differentiation. In two case reports (one heart transplant recipient and one lung transplant recipient), rituximab was a helpful adjunct in the treatment of AHR [35, 36]. TABLE 3 Outcome characteristics Characteristic AHR (n ϭ 23) ACR (n ϭ 75) No REJ (n ϭ 415) Follow-up (days) 764 Ϯ 109 944 Ϯ 58 880 Ϯ 26 2-year graft survival 78%a 85%b 94% 2-year patient survival 95% 95%c 98% Last creatinine, median (IQR) 1.8 (1.4–2.6) 1.5 (1.2–1.9) 1.6 (1.3–1.8) a p ϭ 0.0002 AHR vs. No REJ. b p Ͻ 0.0001 ACR vs. No REJ. c p ϭ 0.013 ACR vs. No REJ. 2-year graft survival (%); 2-year patient survival (%); last creatinine, median (IQR) (mg/dl). 356 R.W. Lehrich et al.
  • 8. Patients who are cross-match positive before transplan- tation are at high risk of developing AHR. IVIG alone, the combination of IVIG and PP, and the combination of IVIG, PP, and rituximab have been used recently as part of desensitization protocols in this patient population [37–41]. These data support additional roles for IVIG and PP, namely the prevention of AHR in high-risk patients and overcoming contraindications for renal transplantation. In summary, we have demonstrated that the combi- nation of IVIG and PP in addition to standard immu- nosuppression containing prednisone, mycophenolate, and calcineurin inhibition effectively salvages renal func- tion in AHR. However, a higher rate of long-term graft loss warrants more investigation into preventive and therapeutic measures. ACKNOWLEDGMENT R.W.L. is funded by a grant from the James R. Clapp Fellow- ship in Nephrology. REFERENCES 1. Platt JL: Acute vascular rejection. Transplant Proc 32: 839, 2000. 2. 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