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Isolated Endarteritis and Kidney Transplant Survival:A Multicenter Collaborative Study

Banu Sis,* Serena M. Bagnasco,† Lynn D. Cornell,‡ Parmjeet Randhawa,§ Mark Haas,|

Belinda Lategan,¶ Alex B. Magil,** Andrew M. Herzenberg,††,a Ian W. Gibson,¶

Michael Kuperman,† Kotaro Sasaki,§ and Edward S. Kraus,‡‡ the Banff Working Group

*Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada; †Departmentof Pathology and ‡‡Department of Medicine, Division of Nephrology, Johns Hopkins University School of Medicine,Baltimore, Maryland; ‡Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota;§Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; |Department ofPathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, California; ¶Department of Pathology,University of Manitoba, Winnipeg, Manitoba, Canada; **Department of Pathology and Laboratory Medicine,University of British Columbia, Vancouver, British Columbia, Canada; and ††Department of Pathology, UniversityHealth Network, University of Toronto, Toronto, Ontario, Canada

ABSTRACTIsolated endarteritis of kidney transplants is increasingly recognized. Notably, microarray studies revealedabsence of immunologic signatures of rejection inmost isolated endarteritis biopsy samples.We investigated ifisolated endarteritis responds to rejection treatment and affects kidney transplant survival. We retrospectivelyenrolled recipientsof kidney transplantwhounderwentbiopsiesbetween1999and2011at sevenAmerican andCanadian centers. Exclusion criteria were recipients were blood group-incompatible or crossmatch-positive orhad C4d-positive biopsy samples. After biopsy confirmation, patients were divided into three groups: isolatedendarteritis (n=103), positive controls (type I acute T cell-mediated rejection with endarteritis; n=101), andnegative controls (no diagnostic rejection; n=103). Primary end points were improved kidney function afterrejection treatment and transplant failure. Mean decrease in serum creatinine from biopsy to 1 month afterrejection treatment was 132.6mmol/L (95% confidence interval [95%CI], 78.7 to 186.5) in patients with isolatedendarteritis, 96.4 mmol/L (95% CI, 48.6 to 143.2) in positive controls (P=0.32), and 18.6 mmol/L (95% CI, 1.8 to35.4) in untreated negative controls (P,0.001). Functional improvement after rejection treatment occurred in80%ofpatientswith isolatedendarteritis and81%ofpositivecontrols (P=0.72).Over themedian3.2-year follow-up period, kidney transplant survival rates were 79% in patients with isolated endarteritis, 79% in positivecontrols, and 91% in negative controls (P=0.01). In multivariate analysis, isolated endarteritis was associatedwith an adjusted 3.51-fold (95% CI, 1.16 to 10.67; P=0.03) risk for transplant failure. These data indicate thatisolated endarteritis is an independent risk factor for kidney transplant failure.

J Am Soc Nephrol 26: 1216–1227, 2015. doi: 10.1681/ASN.2014020157

CKD is common, with estimated prevalence of 8%–

16% worldwide and increased risk for overall andcardiovascular mortality and end stage kidney dis-ease.1,2 Kidney transplantation is the best treatmentfor end stage kidney failure, providing survival andquality of life benefits,3 but transplant rejection re-mains the main complication. Despite achievingdramatically decreased acute rejections within thefirst year and superb kidney transplant survival ratesat 1 year, the 10-year survival rate is still only 45%.1,3

Received February 10, 2014. Accepted August 4, 2014.

aDeceased.

Published online ahead of print. Publication date available atwww.jasn.org.

Correspondence: Dr. Banu Sis, Li Ka Shing Centre for HealthResearch Innovation, Office 3-126A, University of Alberta,Edmonton, AB, Canada T6G 2E1. Email: [email protected]

Copyright © 2015 by the American Society of Nephrology

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mailto:[email protected]

Etiopathologic studies reveal alloimmune responses as themajorcause of late kidney transplant failure.4–7

Isolated endarteritis of kidney transplants is a newly re-ported and increasingly recognized entity.8 Cohort studiesidentified patients whose transplanted kidneys stopped work-ing effectively in association with isolated endarteritis.9–14

Since its first report in 2007, many patients with isolated en-darteritis and a paucity of tubulointerstitial inflammation havebeen described.8–14 Intriguingly, three large genomic studiesperformed in independent cohorts of .700 recipients of kid-ney transplants reported minimal transcriptional activity of Tlymphocytes, cytokines, and chemokines in kidney transplantbiopsies that had isolated endarteritis, detected by microscopicexamination, and proposed that isolated endarteritis does notrepresent true acute T cell-mediated transplant rejection.9–11

There is no evidence-based knowledge on morbidity, treat-ment, and prognosis of isolated endarteritis. The internationalBanffclassificationdefines typesofacuteTcell-mediatedrejectionas types I (tubulointerstitial rejectionwithat leastmoderategradesof both tubulitis and interstitial inflammation), II (vascularrejection with intimal endarteritis), and III (transmural endar-teritis/necrosis).15 Because of the lack of evidence on clinicaloutcomes, Banff schema does not specifically address how tointerpret isolated endarteritis.

As the Banff Working Group, we performed a multicentercollaborative study to investigate if isolated endarteritisresponds to anti–T cell-mediated rejection treatment and af-fects kidney transplant survival.

RESULTS

PatientsSeven transplant centers in the United States and Canadaretrospectively enrolled 307 recipients of kidney transplantsbiopsied between 1999 and 2011. The patients were dividedinto three diagnostic groups after confirmation by expertpathology committee biopsy review: 103 patients with isolatedendarteritis, 101 positive control patients with type I acuteT cell-mediated rejectionwith endarteritis (type I plus type II orIII: tubulointerstitial rejectionandendarteritis), and103negativecontrol patients with no diagnostic rejection. Key exclusion cri-teria for all groups were diffuse or focal peritubular capillarycomplement C4d deposition detected by immunofluorescenceor immunohistochemistry, bloodgroupABOincompatibility, orcrossmatch positivity between donor and recipient. Eligibilitycriteria differed between the study groups. In group 1, patientswere eligible if they had isolated endarteritis defined by Banfflesion scores16 in biopsies and an arteritis score of at least 1with atubulitis score of 0 or 1 and an interstitial inflammation score of0 or 1. In group 2 (positive controls), patientswere eligible if theyhad type I acute T cell-mediated rejection with endarteritis withan arteritis score of at least 1 and both tubulitis and interstitialinflammation scores of 2 or 3. In group 3 (negative controls),patients were eligible if they had no diagnostic rejection defined

as an arteritis score of 0 and both tubulitis and interstitial in-flammation scores of 0 or 1. Only one biopsy per patient wasincluded (if there were multiple biopsies, the earliest biopsy ful-filling eligibility criteria was selected).

The median incidence of isolated endarteritis (C4d nega-tive) per transplant center was 1.3% in all allograft biop-sies from recipients who were blood group-compatible andcrossmatch-negative (mean=1.2, SEM=0.3, minimum=0.2,maximum=2.1).

Table 1 shows the characteristics of patients at the time oftransplantation and biopsies. All groups were donor cross-match-negative and donor blood group-compatible on simi-lar maintenance immunosuppression regimens, and none hadpositive C4d staining in biopsies. Interestingly, T cell depletioninduction therapy at transplantation was more frequent inpatients with isolated endarteritis than positive controls butsimilar to negative controls (19.4% versus 3.0% versus 13.6%,respectively). Themedian time from transplantation to biopsywas 42 days in isolated endarteritis, 59 days in positive con-trols, and 37 days in negative controls (P.0.05). Biopsies per-formed within the first 1 year after transplantation and after1 year were 76% and 24% in isolated endarteritis, 76% and 24%in positive controls, and 79% and 21% in negative controls,respectively (P=0.87). Isolated endarteritis was often associatedwith increased serum creatinine, similar to positive and negativecontrols. However, protocol biopsies were more frequent in iso-lated endarteritis than in positive controls but not in negativecontrols (12.6% versus 3.0% versus 21.4%, respectively). De-layed graft functionwas alsomore frequent in isolated endarter-itis than in positive controls but not in negative controls (14.6%versus 3.0% versus 7.8%, respectively).

Of 307 patients, 117 patients had available donor-specificHLA antibody (DSA) data in the peribiopsy period (median=4days, range=0–90 days). The frequency of positive DSA wassimilar among groups: 18.3% of patients with isolated endar-teritis, 20.8% of positive controls, and 18.2% of negative con-trols (P=0.95).

Morphologic Signatures in BiopsiesIsolated endarteritis (Figure 1A) is defined as localized arteritisin the absence of diagnostic tubulointerstitial rejection (Banfftype I acute T cell-mediated rejection).8 Positive controls in-cluded biopsies with type I acute T cell-mediated rejectionwith endarteritis, and negative controls included biopsieswithout diagnostic rejection showing normal histology(n=30), acute tubular injury (n=30), or borderline (n=34)or trivial (n=9) inflammation below the diagnostic cutofffor rejection according to international criteria.15,16

We compared the grades of morphologic abnormalities indifferent microcompartments of biopsies (Figure 1B). Patientswith isolated endarteritis comparedwith negative controls hadmore arteritis, tubulointerstitial inflammation, microvascularinflammation (sum of glomerulitis and capillaritis scores),transplant glomerulopathy, and arteriosclerosis but negligiblekidney fibrosis. Patients with isolated endarteritis compared

J Am Soc Nephrol 26: 1216–1227, 2015 Isolated Endarteritis 1217

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with positive controls had a similar degree of arteritis, lesstubulointerstitial inflammation and capillaritis, and moretransplant glomerulopathy, arteriosclerosis, and glomerulitis.The grade of arteritis was v1, v2, or rarely, v3 in 92%, 7%, and1% in patients with isolated endarteritis compared with 93%,5%, and 2% in positive controls, respectively (P=0.72). Thefrequency of transplant glomerulopathy was slightly higher inpatients with isolated endarteritis (17%) than positive (10%)or negative (6%) controls (P=0.05). The findings that 17% of pa-tients with isolated endarteritis had transplant glomerulopathyin the same biopsy and that 18.3% of patients with isolated

endarteritis had concurrent DSA suggest that some isolatedendarteritis cases were associated with antibody-mediatedinjury.

Primary End PointsResponse after Rejection TreatmentThe number of patientswho received bolus corticosteroids andT cell depletion did not differ between isolated endarteritis andpositive control groups. However, more patients received in-travenous Ig or plasmapheresis in the isolated endarteritisgroup than inpositivecontrols (9.7%versus1.0%, respectively).

Table 1. Demographic and clinical characteristics of the study population

CharacteristicAll Patients(n=307)

IsolatedEndarteritis

(Group1; n=103)

Type I AcuteT Cell-MediatedRejection withEndarteritis

(Group 2; n=101)

No DiagnosticRejection (Group 3;

n=103)

P ValueGroup 1Versus 2

P ValueGroup 1Versus 3

Recipient age, yr 48.3615.4 49.0616.5 47.5616.1 48.2613.3 0.52 0.71Recipient sex, % women 106 (34.5) 34 (33.0) 36 (35.6) 36 (35.0) 0.69 0.77Primary disease, n (%)Diabetes 62 (20.2) 27 (26.2) 19 (18.8) 16 (15.5) 0.21 0.06Hypertension 35 (11.4) 11 (10.7) 6 (5.9) 18 (17.5) 0.22 0.16Glomerular disease 114 (37.1) 28 (27.2) 42 (41.6) 44 (42.7) 0.03 0.02Other 96 (31.3) 37 (35.9) 34 (33.7) 25 (24.3) 0.74 0.07

Donor age, yr 43.3614.8 42.8615.8 41.2615.1 45.2613.5 0.52 0.27Donor sex, % women 139 (45.3) 48 (46.6) 45 (44.6) 46 (44.7) 0.96 0.23Donor type, % deceased 92 (30.0) 41 (39.8) 28 (27.7) 23 (22.3) 0.46 0.02Retransplant, n (%) 38 (12.4) 20 (19.4) 11 (10.9) 7 (6.8) 0.11 0.01Cold ischemia time, h 28.7613.5 31.7612.5 23.1613.7 29.8614.0 0.04 0.64Induction, % T cell depletion 37 (12.1) 20 (19.4) 3 (3.0) 14 (13.6) 0.001 0.52Corticosteroid use, n (%) 266 (86.6) 90 (87.4) 94 (93.1) 82 (79.6) 0.87 0.13Calcineurin inhibitor use, n (%) 276 (89.9) 93 (90.3) 88 (87.1) 95 (92.2) 0.46 0.62Antiproliferative use, n (%) 265 (86.3) 90 (87.4) 83 (82.2) 92 (89.3) 0.30 0.66Follow-up, mo 55.4635.7 54.1639.1 58.0635.3 54.1632.4 0.47 0.99Indication for biopsy, n (%)Increased serum creatinine 146 (47.6) 48 (46.6) 59 (58.4) 39 (37.9) 0.09 0.21Delayed graft function 26 (8.5) 15 (14.6) 3 (3.0) 8 (7.8) 0.005 0.19Follow-up biopsy after acute

rejection therapy13 (4.2) 6 (5.8) 2 (2.0) 5 (4.9) 0.28 .0.99

Protocol biopsy 38 (12.4) 13 (12.6) 3 (3.0) 22 (21.4) 0.02 0.14Clinical, not specified/other 84 (27.4) 21 (20.4) 34 (33.7) 29 (28.2) 0.03 0.19

Time from transplantationMedian 49 d 42 d 59 d 37 d 0.42 0.64Range 2 d to 13 yr 3 d to 12 yr 2 d to 13 yr 4 d to 8 yr

Serum creatinine at admission,mmol/L

Median 221.0 212.2 247.5 203.3 0.56 0.82Range 53.0–1821.0 79.6–1175.7 88.4–1821.0 53.0–1060.8

DSA in peribiopsy sera, n (%)Anticlass I 11 of 117 (9.4) 7 of 60 (11.7) 2 of 24 (8.3) 2 of 33 (6.1) .0.99 0.49Anticlass II 16 of 112 (14.3) 7 of 55 (12.7) 4 of 24 (16.7) 5 of 33 (15.2) 0.73 .0.99

Rejection treatment, n (%) 227 (73.9) 87 (84.5) 98 (97.0) 42 (40.8) 0.003 ,0.001Corticosteroids 188 (61.2) 73 (70.9) 77 (76.2) 38 (36.9) 0.39 ,0.001Antithymocyte globulin or OKT3 72 (23.5) 26 (25.2) 38 (37.6) 8 (7.8) 0.06 ,0.001IVIG or plasmapheresis 11 (3.6) 10 (9.7) 1 (1.0) 0 (0) 0.001 0.002

Treated before biopsy, n (%) 27 (8.8) 13 (12.6) 7 (6.9) 7 (6.8) 0.17 0.16

Values that are 6 are means6SDs. OKT3, anti-CD3; IVIG, intravenous immunoglobulin.

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Overall, the isolated endarteritis group re-ceived rejection treatment less frequentlythan positive controls (84.5% versus 97.0%,respectively) (Table 1).

Kidney functional response after re-jection treatment was defined by an im-provement in renal function by a positiveD creatinine value (difference between theserum creatinine value at biopsy and theserum creatinine value at 1 or 6 monthsafter biopsy). Functional response rate af-ter rejection treatment was 80% in patientswith isolated endarteritis and 81% in pos-itive controls (P=0.72). Some patients withborderline inflammation or acute tubularinjury had received empirical rejectiontreatment; therefore, kidney functional re-sponse after treatment of isolated endar-teritis or in positive controls was comparedwith 30 untreated patients whose biopsiesshowed normal histology. Rejection treat-ment was associated with a significant de-cline in serum creatinine at 1 and 6monthsin both isolated endarteritis and positivecontrol groups compared with the un-treated negative control group with nor-mal histology (Figure 2). Mean decline inserum creatinine at 1 month was 132.6mmol/L (95% confidence interval [95%CI], 78.7 to 186.5) in patients with isolatedendarteritis and 96.4 mmol/L (95% CI,48.6 to 143.2) in positive controls com-pared with 18.6 mmol/L (95% CI, 1.8 to35.4) in patients who were not treated.This functional improvement was main-tained at 6 months (mean decline in serumcreatinine, 131.7 mmol/L; 95% CI, 80.4 to183.9 in patients with isolated endarteritisand mean decline in serum creatinine,115.8 mmol/L and 95% CI, 75.1 to 157.4in positive controls compared with meandecline in serum creatinine, 30.9 mmol/L;95% CI, 0.9 to 61.9 in untreated controls).

Prognostic Significance of Isolated EndarteritisThe median follow-up after biopsy was 3.2years (range=0–13 years) and similaramong the three groups (P=0.32). Figure3, A and B shows the Kaplan–Meier esti-mates of 3- and 8-year kidney transplantsurvival according to the study groups. At1 year, kidney transplant survival was 90%in patients with isolated endarteritis, 91%in positive controls, and 97% in negativecontrols (P=0.06). At 3 and 8 years, kidney

Figure 1. Morphologic phenotypes in isolated endarteritis and control groups. (A) Mi-crograph showing isolated endarteritis involving an interlobular renal artery, which is anend artery and the only supply of oxygenated blood to a portion of kidney cortex. Arrowspoint subendothelial intimal mononuclear leukocyte infiltration (hematoxylin and eosin).Original magnification, 3400. (B) Comparison of pathology phenotypes associated withisolated endarteritis and control groups. Complement C4d deposition scores were notshown, because C4d-positive biopsies were excluded per study criteria.



transplant survival was 85% and 81% in patients with isolatedendarteritis, 87% and 79% in positive controls, and 96% and92% in negative controls, respectively (P=0.01 and P=0.02,respectively). Over the entire follow-up period (median=3.2years), kidney transplant survival was 79% in patients withisolated endarteritis, 79% in positive controls, and 91% innegative controls (P=0.01).

In univariate analysis, risk for kidney transplant failure was3.96-fold higher in patients with isolated endarteritis and 3.39-fold higher in positive controls compared with negativecontrols (Table 2).

In bivariate risk adjustments, there was a negative associ-ation between kidney transplant survival and isolated endar-teritis and positive controls compared with negative controlswhen separately adjusted for several recipient and donorvariables, delayed graft function, and biopsy findings (Figure3C). In contrast, the poor prognostic value of isolated endar-teritis and type I acute T cell-mediated rejection with endar-teritis lost significance when adjusted for functional responseafter rejection treatment (hazard ratio [HR] for failure at3 years decreased from 3.96 to 1.03 in patients with isolatedendarteritis and from 3.39 to 1.13 in positive controls) (Figure3C), likely reflecting the beneficial effect of functional recoveryafter rejection treatment, which was seen in approximately80% of endarteritis groups.

Independent Predictors of Kidney Transplant FailureTable 2 lists the association of demographic, clinical, morpho-logic, and immunologic factors with kidney transplant failure

in all 307 patients using complete univariate analysis and twomultivariate Cox regression models. In all three groups withavailable antibody testing (n=117), positive DSA was not asignificant prognostic indicator.

Multivariate analysis of 3- and 8-year survival included thestudy groups and the most important three covariates withlowest P values in univariate survival analysis (recipient age,transplant glomerulopathy, and functional response aftertreatment). None of the variables entered into multivariateanalysis were collinear or highly correlated. To see the effectof response after rejection treatment, we built two models:with and without functional response after treatment. Multi-variate models were limited to three variables to avoid modeloverfitting. In model 1, independent predictors of kidneytransplant loss included recipient age (HR, 0.98; 95% CI,0.96 to 1.00), transplant glomerulopathy (HR, 2.31; 95% CI,1.02 to 5.24), type I acute T cell-mediated rejection with en-darteritis (HR, 3.30; 95% CI, 1.08 to 10.14), and isolated en-darteritis (HR, 3.51; 95%CI, 1.16 to 10.67). Inmodel 2, whichincluded the study groups, transplant glomerulopathy, andresponse to treatment, functional response after rejectiontreatment at 6 months was independently associated with adecreased risk compared with patients who were treated buthad no response (HR, 0.28; 95% CI, 0.10 to 0.76). In model2, isolated endarteritis and type I acute T cell-mediated re-jection with endarteritis lost their poor prognostic signifi-cance. The beneficial effect of response after treatment wasmaintained at 8 years.

Multivariate analysis repeated with all variables withP,0.05 in univariate survival analysis for the entire follow-up period (median=3.2 years) provided the same conclusionsas above (Supplemental Tables 1 and 2).

Factors Affecting Survival of Kidneys with Isolated EndarteritisIn the isolated endarteritis group,DSA, clinical versus protocolbiopsy, v scores, interstitial inflammation score of 0 versus 1,and tubulitis score of 0 versus 1were not significant risk factorsat 3 and 8 years (P.0.05). The frequencies of transplant losswere 17% and 21% if isolated endarteritis was detected inprotocol or clinical biopsies, respectively (P.0.05).

Transplant failure was seen in 25% of patients with un-treated isolated endarteritis (3 of 12; at 1.1, 2.2, or 8.8 yearsafter biopsy), 11% (6 of 55) of patients with treated isolatedendarteritis with functional response, and 28% (7 of 25) ofpatients with treated isolated endarteritis without functionalresponse. (Because few patients had follow-up data after8 years, the survival analysis was done using data at 8 years.)At 8 years, kidney transplant survival was 83% in patients withuntreated isolated endarteritis, 91% in patients with treatedisolated endarteritis with functional response, 71% in patientswith treated isolated endarteritis with no functional response,and 92% in negative controls (overall log rank P=0.02) (Figure4). Although patients with untreated isolated endarteritishad shorter transplant survival than patients with treatedisolated endarteritis with functional response (83% versus

Figure 2. Functional response after rejection treatment in iso-lated endarteritis and positive controls. Kidney functional changesfrom biopsy to 1 and 6 months in patients who received rejectiontreatment (isolated endarteritis or type I acute T cell-mediatedrejection with endarteritis) compared with untreated patients withnormal histology in biopsies.



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91%, respectively), this comparison did not reach statisticalsignificance (pairwise log rank P=0.49). However, patientswith treated isolated endarteritis with functional responseshowed better transplant survival compared with patientswith treated isolated endarteritis without functional response(91% versus 71%, respectively; pairwise log rank P=0.03).

We also analyzed if isolated endarteritis was biased byantibody-mediated rejection (ABMR)by two approaches. First,we reclassified all patients (all C4d negative) according to therecently updated Banff 2013 criteria, which no longer includeC4d positivity as a requirement for ABMR diagnosis.17 Bi-opsies with glomerulitis+peritubular capillaritis$2 withglomerulitis.1 or transplant glomerulopathy.0 were classi-fied as suspicious for ABMR, and biopsies with glomerulitis+peritubular capillaritis=0 or 1 and transplant glomerulopathy=0were classified as no evidence for ABMR. We then excludedpatients who met the aforementioned criteria for suspiciousfor ABMR (53 of 307) from survival analysis. At 8 years, kidneytransplant survival was 81% in patients with isolated endarteritiswith no evidence for ABMR, 86% in positive controls without

evidence for ABMR, and 93% in negative controls (log rankP=0.02) (Figure 5). Second, we repeated survival analysis ofstudy groups in patients who were DSA-negative. Of 117patients tested for DSA, 22 patients had positive DSA, and95 patients did not have DSA. Within patients who were neg-ative for DSA, kidney transplant survival at 8 years was 77.6%in patients with isolated endarteritis, 88.9% in positive con-trols, and 96% in negative controls (P=0.09) (Figure 6). Tak-ing both analyses together, these data suggest that negativeprognostic effect of isolated endarteritis is likely not biasedby ABMR.

DISCUSSION

In this multicenter, collaborative, diagnostic, controlled studyof 307 patients, isolated endarteritis was detected in 103patients and associated with an adverse effect on long-termkidney transplant outcomes. The risk for kidney transplantfailure was 3.51-fold higher in patients with isolated

Figure 3. Negative effect of isolated endarteritis on kidney transplant survival. (A and B) Kidney transplant survival curves at (A) 3 and(B) 8 years after biopsy-confirmed diagnosis (Kaplan–Meier analyses). (C) Forest plots of adjusted HRs of risk of transplant failure in patientswith isolated endarteritis (red box) or type I acute T cell-mediated rejection (blue circle) with endarteritis according to separate clinicalcovariates compared with the reference control population (no rejection; Cox regression analyses).



Table 2. Univariate and multivariate analyses of kidney transplant survival in all patients of three groups

Variable3-yr Survival 8-yr Survival

HR (95% CI) P Value HR (95% CI) P Value

Univariate analysesDonor age, yr 1.01 (0.98 to 1.04) 0.68 1.01 (0.98 to 1.03) 0.54Recipient age, yr 0.98 (0.95 to 1.00) 0.02 0.97 (0.96 to 0.99) 0.004Donor typeLiving 1.0 1.0Deceased 3.05 (1.13 to 8.22) 0.03 2.21 (0.98 to 4.96) 0.06

Repeat transplantNo 1.0 1.0Yes 1.28 (0.49 to 3.34) 0.61 1.57 (0.77 to 3.17) 0.21

Delayed graft functionNo 1.0 1.0Yes 2.57 (1.06 to 6.24) 0.04 1.87 (0.87 to 4.02) 0.11

DSA at time of biopsyAbsent 1.0 1.0Present 0.78 (0.17 to 3.51) 0.74 1.22 (0.34 to 4.36) 0.77

Biopsy typeProtocol 1.0 1.0Clinical 2.02 (0.48 to 8.46) 0.34 2.53 (0.61 to 10.45) 0.20

Microvascular inflammation sum scoreLow: 0 or 1 1.0 1.0High: 2–6 1.48 (0.70 to 3.12) 0.31 1.83 (1.02 to 3.32) 0.05

Transplant glomerulopathyNo 1.0 1.0Yes 2.83 (1.27 to 6.30) 0.01 3.18 (1.65 to 6.16) 0.001

Interstitial fibrosis and tubular atrophy sum scoreLow: 0 or 1 1.0 1.0High: 2–6 2.24 (1.10 to 4.53) 0.03 1.87 (1.05 to 3.31) 0.03

Rejection therapyNone 1.0 1.0Steroids only 1.76 (0.59 to 5.27) 0.31 1.96 (0.81 to 4.75) 0.14T cell depletion6steroids 2.32 (0.73 to 7.39) 0.16 1.79 (0.67 to 4.77) 0.25

Response to rejection therapy at 1 mo after biopsya

No 1.0 1.0Yes 0.74 (0.27 to 2.02) 0.55 0.62 (0.29 to 1.32) 0.21


No 1.0 1.0Yes 0.28 (0.10 to 0.76) 0.01 0.38 (0.18 to 0.81) 0.01

Study groupsNo rejection 1.0 1.0Isolated endarteritis 3.96 (1.31 to 11.93) 0.01 2.66 (1.16 to 6.08) 0.02Type I acute TCMR with endarteritis 3.39 (1.11 to 10.40) 0.03 2.57 (1.14 to 5.80) 0.02

Multivariate analysesModel 1 (three variables entered)Number at risk 296 296Number of failures 32 48Study groupsNo rejection 1.0 1.0Isolated endarteritis 3.51 (1.16 to 10.67) 0.03 2.48 (1.08 to 5.69) 0.03Type I acute TCMR with endarteritis 3.30 (1.08 to 10.14) 0.04 2.63 (1.16 to 5.93) 0.02

Recipient age, yr 0.98 (0.96 to 1.00) 0.04 0.98 (0.96 to 0.99) 0.009Transplant glomerulopathyNo 1.0 1.0Yes 2.31 (1.02 to 5.24) 0.04 2.66 (1.36 to 5.18) 0.004

Model 2 (three variables entered)



endarteritis compared with negative controls after adjustingfor several clinical covariates. Conversely, functional im-provement after the use of corticosteroid-based treatmentwas independently associated with reduced risk of kidneytransplant failure at 3 and 8 years. Response rate after mostlyanti-T cell-mediated rejection treatment was 80% in pa-tients with isolated endarteritis. Therefore, decline in serumcreatinine after corticosteroid-based treatment with or withoutT cell depletion medications seems beneficial in improvingshort-term function and long-term survival of kidney trans-plants with isolated endarteritis, possibly as a result of thetreatment. Our data strongly suggest that isolated endarter-itis behaves as true acute rejection and should be treatedaccordingly.

This study provides the first multicenter, evidence-basedinsights into isolated endarteritis of kidney transplants bycomparing its clinical behavior andoutcomeswith two types of

controls: type I acute T cell-mediated rejection with endarter-itis and no diagnostic rejection. Patients with isolated endar-teritis clinically behaved similarly to positive control patients,in whom inflammatory infiltration involved arteries, tubules,and interstitium of the kidney. Both rejection types oftenmanifested with increased serum creatinine within the first2 months after transplantation. Interestingly, patients withisolated endarteritis had received T cell depletion inductiontherapies more frequently than positive control patients, sug-gesting that isolated endarteritis in some patients representsa therapeutically altered form of rejection with a paucity ofinfiltrating mononuclear leukocytes in the tubulointerstitialcompartment. Survival of kidney transplants with isolatedendarteritis or type I acute T cell-mediated rejection withendarteritis was also comparable with increased incidence oftransplant failures. Less than one fifth of isolated endarteritiswas detected in protocol biopsies from well functioningtransplants or associated with delayed graft function. The in-frequent association between delayed graft function and iso-lated endarteritis might imply a relationship between increasedexposure to donor antigens because of ischemic injury andrejection responses. Endarteritis is not recognized in nativekidneys with ischemic injury; thus, it is unlikely that isolatedendarteritis is simply an injury response per se.

Our data suggest that isolated endarteritis in a nonhighlysensitized population with C4d-negative biopsies commonlyrepresents acute T cell-mediated rejection andmay respond toanti-T cell therapy.Thus, ourdata support theBanff criteria fortype IIT cell-mediated rejection,whichdonot require interstitialinflammation or tubulitis to diagnose rejection. However, C4dnegativity alone cannot exclude ABMR, which was recommen-ded by the recently updated Banff 2013 criteria.17 Despite exclu-sion of C4d-positive biopsies and ABO-incompatible/positivecrossmatch kidneys, 18.3% (11 of 60) of patients with iso-lated endarteritis and available HLA antibody testing hadDSA, and patients with isolated endarteritis had higher

Table 2. Continued

Variable3-yr Survival 8-yr Survival

HR (95% CI) P Value HR (95% CI) P Value

Number at risk 200 200Number of failures 15 28Study groupsNo rejection 1.0 1.0Isolated endarteritis 0.84 (0.19 to 3.61) 0.81 0.82 (0.26 to 2.58) 0.74Type I acute TCMR with endarteritis 1.02 (0.25 to 4.21) 0.98 1.21 (0.42 to 3.46) 0.73

Transplant glomerulopathyNo 1.0 1.0Yes 2.14 (0.60 to 7.68) 0.24 3.30 (1.32 to 8.23) 0.01


No 1.0 1.0Yes 0.28 (0.10 to 0.76) 0.01 0.37 (0.17 to 0.80) 0.01

TCMR, T cell-mediated rejection.aResponse to rejection therapy was entered only in patients who received antirejection treatment, and it was defined as an improvement in renal function bya positive D creatinine value (difference between the serum creatinine value at biopsy and the serum creatinine value at 1 or 6 months after biopsy).

Figure 4. Effect of treatment on survival of kidneys with isolatedendarteritis. Kidney transplant survival curves at 8 years afterbiopsy-confirmed diagnosis are shown (Kaplan–Meier analysis).



frequencies of histologic lesions associated with ABMR (trans-plant glomerulopathy, arteriosclerosis, and glomerulitis) thancontrol groups. However, DSA was not a significant risk factorfor graft failure in isolated endarteritis or all three groups. Thisfinding aligns with several large studies, which reported thatnot all DSAs are risk factors and that the majority of patientswith DSA maintains long-term outcomes similar to patientswho are not sensitized.18–21 In patients who are highly sensi-tized or have C4d-positive biopsies, however, frequency andeffect of DSA-associated isolated endarteritis may be higher.The higher frequency of patients who were tested for DSA andtreated with antiantibody strategies in the isolated endarteritisgroup compared with controls (despite similar rates of DSApositivity in the three groups) suggests that some cliniciansviewed isolated endarteritis as antibody-mediated, at least inpart. Indeed, two recent small series, in which 5 of 13 and 5 of6 patients with isolated endarteritis had DSA, seem to supportthis notion.12,13 Furthermore, Lefaucheur et al.22 found that45% of patients with DSA and endarteritis did not recoverwith anti-T cell treatment and that most patients lost theirtransplanted kidneys. In the study by Lefaucheur et al.,22

82% of endarteritis with DSA was with v1 or v2 lesions, 44%of patients were C4d-positive, and most patients had micro-vascular inflammation, interstitial inflammation, and tubulitis,consistent with mixed acute rejection. Therefore, in patients

with isolated endarteritis, DSA, and microvascular inflamma-tion, adding anti-B cell/antibody-depleting strategies to corti-costeroids may prolong graft survival, although this still needsto be examined.

Isolated endarteritis became increasingly recognized after amicroarray study reported minimal inflammatory gene ex-pression signatures of negligible T cell activation, IFN-g, andchemokines in association with isolated endarteritis in thesame biopsy.9 This finding was later validated in independentpatient cohorts and microarray-classifier diagnosed biopsieswith isolated endarteritis as negative for T cell-mediated rejec-tion.10,11We interpret thesemolecularfindingswith caution. Theclassifiers were trained in index rejection biopsies with high in-flammation (spectrum bias). Thus, establishment of gene signa-ture classifiers to diagnose acute rejectionwould likely require useof a wide range of rejection states and not just extreme cases.Another potential explanation is that molecular tests gave false-negative results in biopsies with isolated endarteritis because ofsampling error, because negative molecular signatures were de-tected in one core and isolated endarteritis was microscopicallydetected in another core of the same biopsy.

We questioned why kidneys with isolated endarteritis andtype I acute T cell-mediated rejectionwith endarteritis were atincreased risk for failure, especially if T cell-mediated rejectionis a treatable disease and has no poor prognostic significanceaccording to recent studies.22–24 The answer is that not allpatients with endarteritis improve renal function after corti-costeroids or T cell depletion therapies. Approximately 20%of patients in both groups of endarteritis did not show func-tional improvement after therapy, and 15%–17% of patientsprogressed to kidney transplant failure. Conversely, patientsresponding to therapy had less kidney transplant loss (5%).

Figure 5. Prognostic impact of isolated endarteritis in patientswithout evidence for ABMR. Survival of isolated endarteritis afterexclusion of patients with ABMR histologic features according tothe recently updated Banff 2013 criteria. Patients with glomerulitis(g)+peritubular capillaritis (ptc) sum score$2 with g.1 or trans-plant glomerulopathy (cg) score.0 are classified as suspicious forABMR, and patients with g+ptc=0 or 1 and cg=0 are classified asno evidence for ABMR. We excluded patients who met theaforementioned criteria for suspicious for ABMR from survivalanalysis. Kidney transplant survival curves at 8 years in patientswithout evidence for ABMR are shown (Kaplan–Meier analysis).

Figure 6. Prognostic impact of isolated endarteritis in patientswho were DSA-negative. Kidney transplant survival curves at 8years in patients with no detectable DSA are shown (Kaplan–Meieranalysis).



This finding was confirmed in multivariate survival analysis:adjustment for response to treatment significantly decreasedthe risk for transplant loss. Our results seem consistent with arecent report of 11 patients with isolated endarteritis who hadpoor long-term outcomes.14 It is noteworthy to differentiateour results from the belatacept phase III trial, which showedhigher rates of early endarteritis (18% versus 4%) and slightlyless DSA (4% versus 7%) but superior renal function andcomparable graft survival through 5 years in patients treatedwith belatacept versus cyclosporin, respectively.24–26 An-other study indicated that patients treated with belatacepthad more T-regulatory cells in biopsies during rejectioncompared with patients treated with calcineurin inhibi-tor,27 suggesting that belataceptmay ease recovery from acuterejection by selective immune regulation. In contrast, mostpatients in our cohort were on calcineurin inhibitors, andendarteritis unresponsive to anti-T cell therapy was a poorprognostic indicator.

In conclusion, this study provides the first evidence-basedclinical knowledge on isolated endarteritis in a large popula-tion. This is important, because there are currently no guide-lines for diagnostic interpretation and treatment of isolatedendarteritis. Our data indicate that isolated endarteritis shouldbe diagnosed and treated as acute rejection to prevent long-term kidney transplant failure.

CONCISE METHODS

PatientsAt seven American and Canadian centers, we retrospectively enrolled

patients who underwent kidney transplantation and developed biopsy-

proven isolated endarteritis, type I acute T cell-mediated rejectionwith

endarteritis (type I plus type II or III: tubulointerstitial rejection and

endarteritis), or no diagnostic rejection between January of 1999 and

December of 2011. Only one biopsy per patient was included (if there

were multiple biopsies, the earliest biopsy fulfilling eligibility criteria

was selected).

Eligibility criteria differed between the study groups. In group 1,

patients were eligible if they had isolated endarteritis defined by Banff

lesion scores16 in biopsies as an arteritis score of at least 1 with a tubulitis

score 0 or 1 and an interstitial inflammation score 0 or 1. In group

2 (positive controls), patients were eligible if they had type I acute

T cell-mediated rejection with endarteritis with an arteritis score of at

least 1 and both tubulitis and interstitial inflammation scores of 2 or 3.

In group 3 (negative controls), patients were eligible if they had no

diagnostic rejection defined as an arteritis score of 0 and both tubulitis

and interstitial inflammation scores of 0 or 1.

Key exclusion criteria for all groups were diffuse or focal

peritubular capillary complement C4d deposition detected by

immunofluorescence or immunohistochemistry, blood group

ABO incompatibility, or crossmatch positivity between donor and

recipient. Biopsies with GN or thrombotic microangiopathy were

excluded. Biopsies processed at each site within 2 months of the

submission date of biopsies with isolated endarteritis meeting the

above histopathologic criteria were selected as controls. To exclude

bias in selection of controls, no clinical parameters beyond biopsy

pathology features were matched. The centers included in this study

collected data in compliancewith local ethical and consent guidelines

under approval by their Institutional Review Boards and provided

only deidentified data for this study.

Expert Pathology Committee Review of BiopsySpecimensBiopsies were reviewed, and their morphologic features were scored

using international Banff criteria15,16 by a committee of expert trans-

plant pathologists (B.S., S.M.B., L.D.C., P.R., and M.H.) who were

blinded to the patients’ clinical courses. All biopsies were adequate

according to Banff criteria16 and included at least two cores with two

or more arteries. Biopsies that were confirmed by full consensus

among committee members to meet the histopathologic eligibility

criteria were enrolled.

Study DesignRenal functionwas assessed at 1 and 6months after biopsy, and kidney

transplant survival was determined 1, 3, and 8 years postbiopsy.

In addition, anonymized donor and recipient clinical data at trans-

plantation, maintenance immunosuppressive regimens, treatment of

acute rejection at time of biopsy, and serumHLA antibody test results

in the peribiopsy period were captured from each site for analysis.

Antibody specificities were determined by either Luminex single

antigen beads or FlowPRA single antigen I and II beads (One Lambda,

Canoga Park, CA) after a positive HLA antibody screening test using

FlowPRA beads or Quickscreen ELISA.

End PointsWe had two primary end points: kidney functional response after

rejection treatment, which was indicated by an improvement in renal

function by a positive D creatinine value (difference between the

serum creatinine value at biopsy and the serum creatinine value at

1 or 6 months after biopsy), and kidney transplant failure, which was

defined as return to dialysis and/or retransplantation. Renal func-

tional course after rejection treatment was studied in patients with

endarteritis who received treatment compared with negative controls

with no treatment.

Statistical AnalysesMeans (6SDs), medians and ranges, and 95% CIs were determined

for all continuous variables. All transplants that were functioning at 1,

3, or 8 years were given a censor time of 1, 3, or 8 years and assigned a

transplant status of working, regardless of any failures in the periods

after 1, 3, or 8 years, respectively. Survival analyses were performed

after biopsies with the Kaplan–Meier method using log rank test and

univariate and multivariate models with Cox regression using the

backward stepwise (likelihood ratio) method. The assumption of

proportional hazards over time was verified using the log–log graphic

method andmet by all covariates. Potential linearity of covariates was

investigated by collinearity diagnostics before multivariate survival

analysis. Data analyses were performed using SPSS 22 statistical soft-

ware (IBM, Armonk, NY).



ACKNOWLEDGMENTS

The authors publish this work in memory of A.M.H., a brilliant

nephropathologist and outstanding collaborator, who died in a tragic

accident during the preparationof thismanuscript. The authors thank

Drs. Ruth Sapir-Pichhadze, Rohan John, Joseph Kim, and Segun

Femure (University of Toronto, Toronto, Ontario, Canada) for help

with data retrieval for incidence estimation analysis.

This work was partially supported by research grants fromAstellas

Pharmaceuticals, Canada (to Multicentre Banff Working Group

Trials), Canadian Institutes of Health Research Grant MOP-102705

(to B.S.), and Roche Organ Transplantation Research Foundation

Grant 608390948 (to the Banff Foundation for Allograft Pathology).

DISCLOSURESNone.

REFERENCES

1. US Renal Data System: USRDS 2013 Annual Data Report: Atlas ofChronic Kidney Disease and End-Stage Renal Disease in the UnitedStates, Bethesda, MD, National Institutes of Health, National Instituteof Diabetes and Digestive and Kidney Diseases, 2013

2. Jha V, Garcia-GarciaG, Iseki K, Li Z, Naicker S, Plattner B, Saran R,WangAY, Yang CW: Chronic kidney disease: Global dimension and per-spectives. Lancet 382: 260–272, 2013

3. Gill JS, Tonelli M: Penny wise, pound foolish? Coverage limits on im-munosuppression after kidney transplantation.NEngl JMed 366: 586–589, 2012

4. El-Zoghby ZM, Stegall MD, Lager DJ, Kremers WK, Amer H, Gloor JM,Cosio FG: Identifying specific causes of kidney allograft loss. AmJ Transplant 9: 527–535, 2009

5. Sellarés J, de Freitas DG, Mengel M, Reeve J, Einecke G, Sis B, HidalgoLG, Famulski K, Matas A, Halloran PF: Understanding the causes ofkidney transplant failure: The dominant role of antibody-mediated re-jection and nonadherence. Am J Transplant 12: 388–399, 2012

6. Gaston RS, Cecka JM, Kasiske BL, Fieberg AM, Leduc R, Cosio FC,Gourishankar S, Grande J, Halloran P, Hunsicker L, Mannon R, Rush D,Matas AJ: Evidence for antibody-mediated injury as a major determinantof late kidney allograft failure. Transplantation 90: 68–74, 2010

7. El Ters M, Grande JP, Keddis MT, Rodrigo E, Chopra B, Dean PG,StegallMD, Cosio FG: Kidney allograft survival after acute rejection, thevalue of follow-up biopsies. Am J Transplant 13: 2334–2341, 2013

8. Sis B, Mengel M, Haas M, Colvin RB, Halloran PF, Racusen LC, Solez K,Baldwin WM 3rd, Bracamonte ER, Broecker V, Cosio F, Demetris AJ,Drachenberg C, Einecke G, Gloor J, Glotz D, Kraus E, Legendre C,Liapis H, Mannon RB, Nankivell BJ, Nickeleit V, Papadimitriou JC,Randhawa P, Regele H, Renaudin K, Rodriguez ER, Seron D, Seshan S,Suthanthiran M, Wasowska BA, Zachary A, Zeevi A: Banff ’09 meetingreport: Antibody mediated graft deterioration and implementation ofBanff working groups. Am J Transplant 10: 464–471, 2010

9. Mueller TF, EineckeG, Reeve J, Sis B,MengelM, Jhangri GS, Bunnag S,Cruz J,Wishart D,MengC,BroderickG,KaplanB,HalloranPF:Microarrayanalysis of rejection in human kidney transplants using pathogenesis-based transcript sets. Am J Transplant 7: 2712–2722, 2007

10. Reeve J, Sellarés J, MengelM, Sis B, Skene A, Hidalgo L, de Freitas DG,Famulski KS, Halloran PF: Molecular diagnosis of T cell-mediated re-jection in human kidney transplant biopsies. Am J Transplant 13: 645–655, 2013

11. Halloran PF, Pereira AB, Chang J, Matas A, Picton M, De Freitas D,Bromberg J, Serón D, Sellarés J, Einecke G, Reeve J: Potential im-pact of microarray diagnosis of T cell-mediated rejection in kidneytransplants: The INTERCOM study. Am J Transplant 13: 2352–2363,2013

12. Shimizu T, Tanabe T, Shirakawa H, Omoto K, Ishida H, Tanabe K: Acutevascular rejection after renal transplantation and isolated v-lesion. ClinTransplant 26[Suppl 24]: 2–8, 2012

13. Brown CC, Sebire NJ, Wittenhagen P, Shaw O, Marks SD: Clinicalsignificance of isolated v lesions in paediatric renal transplant biopsies:Muscular arteries required to refute the diagnosis of acute rejection.Transpl Int 27: 170–175, 2014

14. Wu KY, Budde K, Schmidt D, Neumayer HH, Rudolph B: Acute cellularrejection with isolated v-lesions is not associated with more favorableoutcomes than vascular rejection with more tubulointerstitial in-flammations. Clin Transplant 28: 410–418, 2014

15. Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, HalloranPF, Baldwin W, Banfi G, Collins AB, Cosio F, David DS, DrachenbergC, Einecke G, Fogo AB, Gibson IW, Glotz D, Iskandar SS, Kraus E,Lerut E, Mannon RB, Mihatsch M, Nankivell BJ, Nickeleit V,Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Roberts I,Seron D, Smith RN, Valente M: Banff 07 classification of renal allo-graft pathology: Updates and future directions. Am J Transplant 8:753–760, 2008

16. Racusen LC, Solez K, Colvin RB, Bonsib SM, Castro MC, Cavallo T,Croker BP, Demetris AJ, Drachenberg CB, Fogo AB, Furness P, GaberLW, Gibson IW, Glotz D, Goldberg JC, Grande J, Halloran PF, HansenHE, Hartley B, Hayry PJ, Hill CM, Hoffman EO, Hunsicker LG, LindbladAS, Marcussen N, Mihatsch MJ, Nadasdy T, Nickerson P, Olsen TS,Papadimitriou JC, Randhawa PS, Rayner DC, Roberts I, Rose S, Rush D,Salinas-Madrigal L, Salomon DR, Sund S, Taskinen E, Trpkov K,Yamaguchi Y: The Banff 97 working classification of renal allograft pa-thology. Kidney Int 55: 713–723, 1999

17. Haas M, Sis B, Racusen LC, Solez K, Glotz D, Colvin RB, Castro MC,David DS, David-Neto E, Bagnasco SM, Cendales LC, Cornell LD,Demetris AJ, Drachenberg CB, Farver CF, Farris AB 3rd, Gibson IW,Kraus E, Liapis H, LoupyA,Nickeleit V, Randhawa P, Rodriguez ER, RushD, Smith RN, Tan CD, Wallace WD, Mengel M; Banff Meeting ReportWritingCommittee: Banff 2013meeting report: Inclusion of c4d-negativeantibody-mediated rejection and antibody-associated arterial lesions.Am J Transplant 14: 272–283, 2014

18. Wiebe C, Gibson IW, Blydt-Hansen TD, Karpinski M, Ho J, Storsley LJ,Goldberg A, Birk PE, Rush DN, Nickerson PW: Evolution and clinicalpathologic correlations of de novo donor-specific HLA antibody postkidney transplant. Am J Transplant 12: 1157–1167, 2012

19. Dunn TB, Noreen H, Gillingham K, Maurer D, Ozturk OG, Pruett TL,Bray RA, Gebel HM, Matas AJ: Revisiting traditional risk factors for re-jection and graft loss after kidney transplantation. Am J Transplant 11:2132–2143, 2011

20. Djamali A, Muth BL, Ellis TM, Mohamed M, Fernandez LA, Miller KM,Bellingham JM, Odorico JS, Mezrich JD, Pirsch JD, D’Alessandro TM,Vidyasagar V, Hofmann RM, Torrealba JR, Kaufman DB, Foley DP: In-creased C4d in post-reperfusion biopsies and increased donor specificantibodies at one-week post transplant are risk factors for acute re-jection in mild to moderately sensitized kidney transplant recipients.Kidney Int 83: 1185–1192, 2013

21. Djamali A, Kaufman DB, Ellis TM, Zhong W, Matas A, Samaniego M:Diagnosis and management of antibody-mediated rejection: Currentstatus and novel approaches. Am J Transplant 14: 255–271, 2014

22. Lefaucheur C, Loupy A, Vernerey D, Duong-Van-Huyen JP, SuberbielleC, Anglicheau D, Vérine J, Beuscart T, Nochy D, Bruneval P, Charron D,Delahousse M, Empana JP, Hill GS, Glotz D, Legendre C, Jouven X:Antibody-mediated vascular rejection of kidney allografts: A population-based study. Lancet 381: 313–319, 2013

23. Sellarés J, de Freitas DG, Mengel M, Sis B, Hidalgo LG, Matas AJ,Kaplan B, Halloran PF: Inflammation lesions in kidney transplant



biopsies: Association with survival is due to the underlying diseases.Am J Transplant 11: 489–499, 2011

24. Vincenti F, Charpentier B, Vanrenterghem Y, Rostaing L, BresnahanB, Darji P, Massari P, Mondragon-Ramirez GA, Agarwal M, Di RussoG, Lin CS, Garg P, Larsen CP: A phase III study of belatacept-basedimmunosuppression regimens versus cyclosporine in renal transplantrecipients (BENEFIT study). Am J Transplant 10: 535–546, 2010

25. Vincenti F, LarsenCP, Alberu J, Bresnahan B,Garcia VD, Kothari J, LangP, Urrea EM, Massari P, Mondragon-Ramirez G, Reyes-Acevedo R, RiceK, Rostaing L, Steinberg S, Xing J, Agarwal M, Harler MB, CharpentierB: Three-year outcomes from BENEFIT, a randomized, active-controlled,parallel-group study in adult kidney transplant recipients.AmJTransplant12: 210–217, 2012

26. Rostaing L, Vincenti F, Grinyó J, Rice KM, Bresnahan B, Steinberg S,Gang S, Gaite LE, Moal MC, Mondragón-Ramirez GA, Kothari J, Pupim

L, Larsen CP: Long-term belatacept exposure maintains efficacy andsafety at 5 years: Results from the long-term extension of the BENEFITstudy. Am J Transplant 13: 2875–2883, 2013

27. Bluestone JA, Liu W, Yabu JM, Laszik ZG, Putnam A, Belingheri M,Gross DM, Townsend RM, Vincenti F: The effect of costimulatory andinterleukin 2 receptor blockade on regulatory T cells in renal trans-plantation. Am J Transplant 8: 2086–2096, 2008

See related editorial, “Renal Allograft Rejection: Pieces of the Puzzle,” onpages 1004–1005.

This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2014020157/-/DCSupplemental.





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