C4d Deposition without Rejection Correlates with Reduced Early Scarring in ABO-Incompatible Renal Allografts
Mark Haas*,
Dorry L. Segev,
Lorraine C. Racusen*,
Serena M. Bagnasco*,
Jayme E. Locke,
Daniel S. Warren,
Christopher E. Simpkins,
Diane Lepley,
Karen E. King*,
Edward S. Kraus and
Robert A. Montgomery
Departments of * Pathology, Surgery, and Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland
Correspondence: Dr. Mark Haas, Department of Pathology, Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Pathology 712, Baltimore, MD 21287. Phone: 410-614-5631; Fax: 410-614-7110; E-mail: mhaas{at}jhmi.edu
Received for publication March 10, 2008.
Accepted for publication June 25, 2008.
C4d deposition in peritubular capillaries is a specific markerfor the presence of antidonor antibodies in renal transplantrecipients and is usually associated with antibody-mediatedrejection (AMR) in conventional allografts. In ABO-incompatiblegrafts, however, peritubular capillary C4d is often presenton protocol biopsies lacking histologic features of AMR; thesignificance of C4d in this setting remains unclear. For addressingthis, data from 33 patients who received ABO-incompatible renalallografts (after desensitization) were retrospectively reviewed.Protocol biopsies were performed at 1 and/or 3 and 6 mo aftertransplantation in each recipient and at 12 mo in 28 recipients.Twenty-one patients (group A) had strong, diffuse peritubularcapillary C4d staining without histologic evidence of AMR orcellular rejection on their initial protocol biopsies. The remaining12 patients (group B) had negative or weak, focal peritubularcapillary C4d staining. Three grafts (two in group B) were lostbut not as a result of AMR. Excluding these three patients,serum creatinine levels were similar in the two groups at 6and 12 mo after transplantation and at last follow-up; however,recipients in group A developed significantly fewer overallchronic changes, as scored by the sum of Banff chronic indices,than group B during the first year after transplantation. Theseresults suggest that diffuse peritubular capillary C4d depositionwithout rejection is associated with a lower risk for scarringin ABO-incompatible renal allografts; the generalizability ofthese results to conventional allografts remains unknown.
During the past 10 to 15 yr, an increasing number of transplantcenters worldwide have successfully expanded the potential poolof living kidney donors by performing transplants of cross-match–positiveor ABO-incompatible kidneys into recipients who are preconditionedto remove antibodies specific for donor HLA or blood group antigens.1–7A potential risk of such procedures, however, is the continuedpresence or reappearance of such antibodies with resulting antibody-mediatedrejection (AMR) of the graft. In conventional and HLA-incompatiblerenal allografts, the presence of peritubular capillary (PTC)C4d staining on an allograft biopsy, even a protocol biopsyof a stably functioning graft, is usually associated with histologicfeatures of AMR, namely neutrophil and monocyte marginationin PTC and/or thrombotic microangiopathy (TMA).8–12 Furthermore,PTC C4d deposition plus neutrophil margination and/or TMA onprotocol biopsies of HLA-incompatible grafts was found to beassociated with development of chronic changes, including chronictransplant glomerulopathy (TG), providing strong evidence thatthe former changes indeed represent subclinical AMR in thesegrafts.11
By contrast, we and others have noted that the majority of protocolbiopsies of ABO-incompatible grafts show PTC C4d depositionthat is often diffuse but only infrequently associated withhistologic changes of AMR.12–14 The significance of C4dstaining in the absence of these histologic changes remainsunclear.15
In this study, we retrospectively examined renal allograft biopsiesand clinical data from 33 patients who received an ABO-incompatiblerenal allograft after desensitization to remove blood groupantibodies (BGA). Each patient had protocol biopsies 1 and/or3 and 6 mo after transplantation, and most also had 12-mo protocolbiopsies. The specific questions addressed in the study wereas follows: (1) How often, if at all, do patients with early(1- and/or 3-mo) protocol biopsies showing diffuse, strong C4dstaining without histologic changes of rejection subsequentlydevelop AMR, and (2) how do graft function and graft scarringas assessed on 6- and 12-mo protocol biopsies compare in thesepatients versus those whose early protocol biopsies show absentor weak and focal C4d staining?
Of the 33 study patients, 21 had an initial protocol biopsyshowing strong (>1+, 0 to 4+ scale), diffuse PTC C4d stainingwithout histologic evidence of AMR or acute cellular rejection(ACR; Banff ’97 grade 1A or greater); these patients areclassified as group A. Four of the 21 group A patients had borderlineinflammation on their initial protocol biopsy, and six had mild(g1) glomerulitis. Of the remaining 12 patients, comprisinggroup B, six had negative PTC C4d staining on their initialprotocol biopsy, and six had weak (1+) C4d staining involvingan estimated 10 to 25% of PTC present on their initial protocolbiopsy. As with the group A patients, none of the 12 group Bpatients showed significant (PTC score 1) margination of neutrophilsor mononuclear leukocytes in cortical PTC, more than mild glomerulitis(all had g0), or other histologic features of AMR on their initialprotocol biopsy. In addition, none of these 12 biopsies showedACR or even borderline inflammation. Four additional recipientsof ABO-incompatible renal allografts during the study periodhad 1+, diffuse PTC C4d staining on their initial protocol biopsy,but with margination of leukocytes (mononuclear cells and neutrophils)in PTC, consistent with subclinical AMR.11 These four patientswere not included in this study. Notably, none of the 12 patients(group B) whose initial protocol biopsy showed absent or weakand focal PTC C4d had a subsequent protocol biopsy that demonstratedstrong, diffuse C4d without histologic evidence of AMR. By contrast,14 of the 21 group A patients whose initial protocol biopsyshowed strong, diffuse C4d without histologic evidence of AMRor ACR continued to show diffuse C4d staining (>1+ in allbut two) without margination of neutrophils or mononuclear leukocytesin PTC on each subsequent protocol biopsy during the first yearafter transplantation.
Staining for C3d was done on the initial protocol biopsies from16 of the group A patients and all 12 group B patients. Onlytwo biopsies showed PTC C3d, both from group A patients. Inone biopsy, the C3d staining was diffuse, and in the other itwas focal. Interestingly, the one group A patient whose initialprotocol biopsy showed diffuse C3d later developed AMR. Ourprevious results12 suggested that PTC C3d in addition to C4dmay be better correlated with AMR than C4d alone in ABO-incompatiblerenal allografts; however, the number of patients with C3d-positivebiopsies in this study is far too few to draw any clear conclusions.
Table 1 compares demographic and pretransplantation serologicfindings in group A and B patients. There were no significantdifferences between the groups of patients with respect to age,gender, racial composition, mean and median maximum BGA titerbefore desensitization, or numbers of pre- or postoperativeplasmapheresis (PP)/intravenous Ig treatments. Group A had ahigher fraction of allografts from donors of blood group A1,and group B had a higher fraction of patients receiving kidneysfrom blood type B donors, although variations in the distributionof donor blood types among the two groups of recipients didnot reach statistical significance (Table 1). In addition, similarfractions of patients in each group underwent splenectomy orreceived anti-CD20 antibody as part of their desensitizationprotocol.
Table 1. Demographic and serologic data for patient cohortsa
As shown in Table 2, patients in groups A and B had similarmean serum creatinine (SCr) levels at the times of their initial,6-mo, and 12-mo protocol biopsies, as well as at last follow-up,the last excluding one patient in group A and two in group Bwho ultimately lost their grafts. The group A patient was lostto follow-up after postoperative day (POD) 257, at which timehis SCr was 1.6 mg/dl. He later presented on POD 576 with aSCr of 7.0 mg/dl after stopping all immunosuppressive medicationsfor >3 wk. A biopsy at that time showed severe ACR (Banff’97 type 1B, C4d-negative) that did not respond to treatment,and the patient became dialysis dependent. The group B patients’graft losses occurred 27 and 38 mo after transplantation, respectively.Both of these patients had one or more episodes of ACR (Banff’97 grades 2A and 1B, respectively). Both patients alsohad FSGS, clearly representing recurrent disease in one case,although neither patient had a biopsy with diagnostic changesof AMR.
Table 3 compares renal biopsy findings in the groups of patients.All 33 patients had protocol biopsies done at 6 mo after transplantation,although one such biopsy in a group B patient was inadequate,containing only medullary tissue. Nineteen group A patientsand nine group B patients also had a 12-mo protocol biopsy.One patient in group A and three in group B developed AMR associatedwith a rise in SCr (clinical AMR; Table 3) between 3 and 12mo after transplantation. In one of the group B patients, thebiopsy showing clinical AMR was done 28 d after a 3-mo protocolbiopsy showing subclinical AMR. Similar fractions of patientsin groups A and B had one or more biopsies showing ACR (Banff’97 grade 1A or greater) during the first year after transplantation(Table 3). Two group A patients each had three separate biopsiesshowing ACR, and one patient each in groups A and B had twobiopsies with ACR. Incidence rates of BK virus nephropathy andrecurrent glomerular disease (FSGS in each case) were similarin the two groups (Table 3).
Mean chronic sum scores (comprising the sum of Banff indicesfor TG [cg], interstitial fibrosis [ci], tubular atrophy [ct],and arterial intimal fibrosis [cv]) on 6- and 12-mo protocolbiopsies were lower in group A than in group B, and this reachedstatistical significance at 12 mo (Table 3, Figure 1, top).Furthermore, increases in mean chronic sum scores from initialto 6-mo protocol biopsies and from initial to 12-mo protocolbiopsies both were significantly lower in group A patients comparedwith group B patients (Table 3; Figure 1, bottom). In groupA (but not group B), the mean chronic sum score at 6 mo wasnot significantly different from that on the initial protocolbiopsies (P = 0.80 in group A and P = 0.043 in group B by Wilcoxonrank sum test), although the mean score at 12 mo was differentfrom that on the initial protocol biopsies for both groups (P= 0.012 for group A and P = 0.007 for group B).
Figure 1. Comparison of mean chronic sum scores (cg + ci + ct + cv) on 6- and 12-mo protocol biopsies (top) and mean increases in this score from the initial biopsy to the 6- and 12-mo biopsies (bottom) in group A and group B patients. Error bars indicate 1 SD. P values shown all are by the Wilcoxon rank sum test. Mean and SD values are also listed in Table 3.
There were no significant differences between the two patientgroups with respect to individual Banff chronic indices (cg,ci, ct, and cv) at 6 mo after transplantation; however, at 12mo, mean ci and ct scores were significantly lower in groupA than in group B (both 0.74 ± 0.56 versus 1.33 ±0.87; P = 0.043 by Wilcoxon). Mean cg (0.05 ± 0.23 ingroup A, 0.22 ± 0.44 in group B; P = 0.18) and cv (1.00in both groups) scores on the 12-mo protocol biopsies were notdifferent in the two groups.
The findings of this study document that ABO-incompatible renalallografts showing diffuse PTC C4d staining in the presenceof circulating BGA but the absence of histologic features ofAMR or ACR (Banff ’97 grade 1A or greater) on an earlyprotocol biopsy of a stably functioning graft (group A) developsignificantly less overall chronic change, as assessed by themean chronic sum score (cg + ci + ct + cv), than grafts notshowing these findings during the first year after transplantation(group B). Mean ci, ct, and chronic sum scores on 12-mo protocolbiopsies, as well as mean increases in chronic sum score betweeninitial and both 6- and 12-mo protocol biopsies, were significantlylower in group A than in group B. Furthermore, the degree ofchronic change seen in ABO-incompatible grafts showing diffuseC4d staining without evidence of rejection in this study isessentially identical to that reported for conventional (ABO-compatiblewith no preoperative anti-HLA donor-specific antibodies) livedonor renal allografts at 6 to 12 mo after transplantation,16–18taking into account somewhat higher mean baseline levels ofarterial intimal fibrosis (cv) and, to a lesser extent, tubularatrophy (ct) and interstitial fibrosis (ci) in our donor populationthat includes a relatively high fraction of older (50 yr old)donors.19
Our donor population not only had higher mean baseline ci, ct,and cv values but also greater variability in these parametersthan in conventional live-donor transplantation, for which baselinescores are rarely >0 for ci and ct or >1 for cv.18 Itis because of this variability at baseline that we feel justifiedin comparing increases in chronic sum scores between the twopatient groups as well as absolute sum scores at 6 and 12 mo.The relatively short-term nature of our findings and the limitednumber of patients also led us to focus more on chronic sumscores than on individual indices of chronicity (e.g., cg, ct)to demonstrate significant differences between patient groups,acknowledging that a possible drawback of the sum score is thatit treats increases in each of the different indices as beingequivalent, when in actuality increases in different parametersmay have different predictive values regarding graft survival.Still, we did find significant differences in mean ci and ct(but not cg and cv) values at 12 mo between groups A and B.Histologic changes of TG, which is the chronic lesion most closelyassociated with antibodies against the graft,20 are quite uncommon1 yr after transplantation in both conventional and ABO-incompatiblerenal allografts,16,20 although early changes of TG may be detectablewithin 2 mo by electron microscopy.21
Only four of our study patients (one in group A, three in GroupB; P = 0.12) developed diagnostic changes of AMR. This suggeststhat factors other than prevention of morphologically identifiableAMR contribute to the beneficial effect of PTC C4d depositionwithout histologic evidence of rejection in reducing graft scarringduring the first year after transplantation. Perhaps futureuse of microarray22 and/or other molecular methods may proveuseful in identifying possible antibody-mediated graft injuryin the absence of diagnostic morphologic changes of AMR.
It will also be important to investigate whether the apparentbeneficial effect associated with diffuse C4d staining withoutevidence of rejection on relatively short-term graft scarringpersists in the long term and translates into significantlyimproved long-term survival of ABO-incompatible grafts. Especiallyas BGA persist in all of our recipients of ABO-incompatiblerenal allografts, such longer term studies are needed to determinewhether diffuse C4d staining without evidence of rejection trulyreflects a state of graft accommodation, in which the organcontinues to function well despite the presence of antibodiesdirected against it.23 The finding of diffuse PTC C4d stainingwithout histologic evidence of rejection on one or more earlyprotocol biopsies did not preclude later development of AMR,although the latter was rare in this study. Only one of 21 groupA patients compared with three of 12 group B patients developedAMR, although this difference did not reach statistical significanceand no grafts in either group were lost to AMR.
Whereas in the majority of biopsies of ABO-incompatible graftsthe presence of C4d is not associated with histologic changesof AMR, this is not the case in biopsies of ABO-compatible renalallografts, even protocol biopsies.9–11,24–27 Furthermore,in the latter grafts, even PTC C4d deposition without histologicevidence of AMR or ACR may signify low-level, antibody-mediatedgraft injury. In a study by Dickenmann et al.,28 of 22 patientswith ABO-compatible grafts and a biopsy showing such findings,death-censored renal allograft survival 3 yr after biopsy was69% in patients who were not given increased immunosuppression,compared with 100% in those who were. It must therefore be emphasizedthat the findings of our study, namely that PTC C4d depositionwithout histologic evidence of AMR or ACR is associated withless graft scarring during the first year after transplantation,seem to be applicable only to ABO-incompatible renal transplantationand do not represent a general paradigm.
Antibodies directed against the carbohydrate blood group antigensmay well be less likely to promote AMR, including subclinicalAMR, than are antibodies against HLA protein antigens. In theabsence of early T cell help (possibly prevented by multidrugimmunosuppressive therapy), antibodies produced against a carbohydrateantigen structurally similar to human blood group antigens ina mouse heart xenograft model result in graft accommodation,with these antibodies binding to the carbohydrate antigen onthe graft but not producing AMR.29,30 Still, in this model,AMR did occur when antibodies to the same carbohydrate antigenwere produced in the setting of early T cell help,29 and AMR(both clinical and subclinical) does occur in some ABO-incompatiblerenal allografts,12–14,16,31,32 including four (12%) of33 in this study. Conversely, a small number of ABO-compatible,positive cross-match (HLA-incompatible) grafts showed C4d stainingon protocol biopsies without histologic changes of AMR or subsequentdevelopment of graft dysfunction or scarring, including TG.11,12This suggests that factors in addition to the nature of theantigen determine whether a graft exposed to antidonor antibodydevelops AMR or simply shows C4d deposition without rejection.Inhibition of the complement cascade distal to C4 cleavage byfactors such as decay-accelerating factor, CD59, and heparansulfate may play a vital role in determining whether graftsexposed to such antibody develop AMR or show accommodation.23,33,34Indeed, recent studies in a heart xenograft model similar tothat noted already demonstrated elevated expression of decay-acceleratingfactor, CD59, and Crry (a rodent complement regulatory protein)on capillary endothelial cells of accommodating grafts.34 Theregulation of expression of these factors in human allograftsand how this is affected by binding of antibodies against bloodgroup and HLA antigens expressed on the graft remain importantareas for future study.
There are several limitations of this study. First, it is aretrospective study, and patients were not treated accordingto standardized protocols. Still, group A and group B patientswere quite similar with respect to demographics; serology; desensitizationprocedures (mean numbers of PP/intravenous Ig treatments plusfraction of patients undergoing splenectomy and receiving anti-CD20);baseline immunosuppression; and incidence rates of ACR, BK virusnephropathy, and recurrent glomerular disease. Second, as notedalready, follow-up intervals were relatively short, and it willneed to be determined whether the association of diffuse PTCC4d deposition without histologic evidence of AMR with reducedgraft scarring during the first year after transplantation persistsin the long term. Although there is considerable evidence thatdevelopment of chronic histopathologic changes during the firstyear after transplantation is associated with reduced graftsurvival,18,35,36 these studies are in conventional allograftsthat are less likely to be at risk for antibody-mediated graftinjury than are ABO-incompatible grafts.16 Finally, becausethe number of patients studied was relatively small, there ispotential for the results to be disproportionately influencedby just a few patients with poor outcomes. Our "control" groupconsisted of only 12 patients with negative or weak and focalC4d staining on their initial protocol biopsy, two of whom losttheir grafts to causes other than AMR. Thus, as ABO-incompatiblerenal transplantation becomes more widespread, it will be importantto examine correlations between PTC C4d deposition without histologicevidence of AMR and subsequent graft function and histologyin larger patient populations from different transplant centers.
Patients
All patients receiving a live-donor, ABO-incompatible renaltransplant at our center from January 2000 through July 2007were considered for inclusion in this study, with the exceptionof patients receiving both HLA- and ABO-incompatible grafts.Of a total of 45 such recipients, 37 patients met the followinginclusion criteria: (1) One or more protocol biopsies were performedduring the first approximately 3 mo after transplantation andmet adequacy criteria defined in the Banff ’97 workingclassification for renal allograft pathology,37 (2) one or moresubsequent protocol biopsies were performed at 6 and/or 12 moafter transplantation, and (3) C4d staining was done on allprotocol biopsies. Four of the 37 patients had 1+, diffuse PTCC4d staining on their initial protocol biopsy with marginationof leukocytes (mononuclear cells and neutrophils) in PTC, consistentwith subclinical AMR,11 and were not included in this study.
All patients receiving ABO-incompatible renal transplants weretreated before transplantation with every-other-day PP and 100mg/kg cytomegalovirus hyperimmune globulin (CMVIg; Cytogam;Medimmune, Gaithersburg, MD) to remove BGA. PP/CMVIg treatmentswere continued until a BGA titer of 16 was achieved. Detectablelevels of circulating BGA, however, were present throughoutthe postoperative course of each patient. Patients in the earlypart of the study period underwent splenectomy, those in themiddle part received anti-CD20 (Rituxan; IDEC-Genentech, SanFrancisco, CA), usually without splenectomy, and those in thelast part underwent neither splenectomy nor anti-CD20 therapy.Patients also received two to 10 posttransplantation PP/CMVIgtreatments per protocol as described previously.5 In addition,all patients received a sequential quadruple-drug immunosuppressiveregimen consisting of tacrolimus (0.1 mg/kg per d, adjustedto an initial target level of 8 to 12 ng/ml), mycophenolatemofetil (2 g/d), daclizumab (2 mg/kg before reperfusion, then1 mg/kg every other week for a total of five doses), and corticosteroids(methylprednisolone 500 mg intraoperatively and 125 mg every6 h, followed by prednisone 30 mg/d, then 20 mg/d after targetlevel of tacrolimus was reached). All study procedures wereapproved by the institutional review board of Johns HopkinsMedical Institutions.
C4d and C3d Staining
For each biopsy, a 3- to 4-mm portion of renal cortical and/ormedullary tissue was taken for C4d staining. For the majorityof biopsies, staining for C3d was also performed. This stainingwas done by indirect immunofluorescence on cryostat sectionsusing mouse mAb to human C4d and C3d (Quidel, San Diego, CA)as described previously.11,12 Staining for C4d and C3d in PTCwas graded for intensity (0 to 4+ scale, increments of 0.5+)and was also graded as diffuse (estimated 50% of specimen),focal (10% but <50%), or negative (absent or involving <10%of specimen).
Grading of Histologic Parameters and Diagnosis of AMR
Histologic slides from all biopsies performed on the 33 patientsmeeting study criteria were stained with hematoxylin and eosin,periodic acid-Schiff, silver methenamine, and Masson's trichromestains and were reviewed by a renal pathologist (M.H.) who wasblinded to the clinical, immunofluorescence, and serologic data.For each biopsy, margination of leukocytes (neutrophils andmononuclear cells) in cortical PTC was scored according to thefollowing schema15: 0, minimal margination (fewer than threecells in the most involved PTC and/or margination in [estimated]10% of PTC in nonsclerotic cortex present); 1+, marginationin >10% of PTC, with three to four cells in the most involvedPTC cross-sections; 2+, margination in >10% of PTC, withfive to 10 cells in the most involved PTC cross-sections; and3+, margination in >10% of PTC, with >10 cells in themost involved PTC cross-sections. It was also noted for eachbiopsy whether there were histologic findings of TMA, definedby one or more glomerular and/or arteriolar fibrin thrombi,arteriolar necrosis, and/or fragmented red blood cells in oneor more vessel walls. In addition, the Banff ’97 grade(type) of acute rejection, all Banff acute and chronic indices,37and a chronic sum score composed of the sum of the Banff chronicindices (cg + ci + ct + cv) were recorded for all biopsies.A diagnosis of AMR was made when each of the following threecriteria was met: (1) Diffuse PTC C4d staining with intensity1+, (2) PTC margination score 1+ with primarily neutrophilsor a mixture of neutrophils and mononuclear cells and/or presenceof TMA, and (3) presence of BGA in serum with specificity fordonor blood group antigen(s). C4d staining without evidenceof rejection was determined to be present when each of the followingfive criteria were met: (1) Diffuse PTC C4d staining with intensity>1+; (2) PTC margination score of 0 and no evidence of TMA;(3) no concurrent ACR (Banff ’97 grade 1A or greater);(4) Banff g and cg indices of 1 and 0, respectively; and (5)presence of BGA in serum with specificity for donor blood groupantigen(s).
SCr levels at the time of each biopsy and at most recent follow-upwere recorded on spreadsheets separate from those containingthe biopsy results noted and results of serologic tests; thespreadsheets identified each patient only by a study number.Titers of IgG antibodies against blood group antigens were determinedby indirect isoagglutination assay using anti-human globulinas described previously.5 None of the patients in this studywas found to have donor-specific anti-HLA antibodies at anypoint during desensitization or after transplantation.
Statistical Analysis
The significance of differences between sample means was determinedby t test for normally distributed data and by Wilcoxon ranksum test for data that were not normally distributed. Categoricaldata were compared using Fisher exact test. All tests were two-sidedwith statistical significance set at P < 0.05. Statisticalanalyses were performed using Stata 10 statistical softwarefor Linux (Stata Corp., College Station, TX).
This work was supported in part by a grant from the Kidney &Urology Foundation of America, Inc.
A preliminary report of some of these findings was presentedat the 9th Banff Conference on Allograft Pathology; June 23through 29, 2007; La Coruna, Spain.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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N. Kieran, X. Wang, J. Perkins, C. Davis, E. Kendrick, R. Bakthavatsalam, N. Dunbar, P. Warner, K. Nelson, K. D. Smith, et al. Combination of Peritubular C4d and Transplant Glomerulopathy Predicts Late Renal Allograft Failure
J. Am. Soc. Nephrol.,
October 1, 2009;
20(10):
2260 - 2268.
[Abstract][Full Text][PDF]
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Abstract
Introduction
1+) C4d staining involving an estimated 10 to 25% of PTC present on their initial protocol biopsy. As with the group A patients, none of the 12 group B patients showed significant (PTC score 
1) margination of neutrophils or mononuclear leukocytes in cortical PTC, more than mild glomerulitis (all had g0), or other histologic features of AMR on their initial protocol biopsy. In addition, none of these 12 biopsies showed ACR or even borderline inflammation. Four additional recipients of ABO-incompatible renal allografts during the study period had 
-gal IgG1 in a rat-to-mouse model.
Am J Transplant 8
: 32
–40, 2008[Medline]
