through a glass darkly: seeking clarity in preventing late kidney

BRIEF REVIEW wwwjasnorg

Through a Glass Darkly Seeking Clarity in PreventingLate Kidney Transplant Failure

Mark D Stegall Robert S Gastondagger Fernando G CosioDagger and Arthur Matassect

Division of Transplant Surgery Departments of Surgery and Immunology von Liebig Transplant Center Mayo ClinicRochester Minnesota daggerDivision of Nephrology Department of Medicine University of Alabama at BirminghamBirmingham Alabama DaggerDivision of Nephrology and Hypertension Department of Medicine von Liebig TransplantCenter Mayo Clinic Rochester Minnesota and sectDepartment of Surgery University of Minnesota MinneapolisMinnesota

ABSTRACTA common lament is that long-term kidney transplant outcomes remain the samedespite improvements in early graft survival To be fair progress has been mademdashin both our understanding of chronic injury and modestly graft survival How-ever we are still a long way from actually solving this important and difficultproblem In this review we outline recent data supporting the existence of sev-eral causes of renal allograft loss the incidences of which peak at different timepoints after transplantation On the basis of this broadened concept of chronicrenal allograft injury we examine the challenges of clinical trial design in long-term studies including the use of surrogate end points and biomarkers Finallywe suggest a path forward that ultimately may improve long-term renal allograftsurvival

J Am Soc Nephrol 26 20ndash29 2015 doi 101681ASN2014040378

Improving long-term renal allograft sur-vival is one of the major unmet needs inkidney transplantation Approximatelyone-half of graft failures beyond the firstpost-transplant year are caused by death ofthe recipient and certainly this is animportant topic1 However the focus ofthis review is graft failure causedby chronicrenal allograft injury in living patients

Death-censored kidney transplantsurvival has unquestionably improvedover the past quarter century (Figure 1)The half-life of standard criteria de-ceased donor (SCD) kidneys in theUnited States has increased from 106years for those transplanted in 1989 toan estimated 155 years for transplantsperformed in 20051 Similarly over thesame time period the half-life of kidneysfrom living donors (LDs) increased from174 years to an estimated 209 yearsHowever this improvement primarily

reflects a dramatic decline in the per-centage of grafts failing in the first 1year post-transplant decreasing from86 to 45 for LD kidneys and from158 to 51 for SCD kidneys

Unfortunately death-censored attri-tion rates beyond the first year remainrelatively unchanged since 1989mdash3ndash5per year for SCD and 2ndash3 per year forLD kidneys By 10 years 20ndash30 of allrenal allografts will have failed

In recent years our understanding oflate graft failure has changed dramati-cally In this review we outline some ofthe history of the study of chronic graftinjury and summarize data leading toour model We then critically examinethe recent approaches to the study oflong-term injury (for example the useof surrogate end points) and suggesthow novel treatment trials might beconstructed going forward

HYPOTHESES REGARDINGCHRONIC RENAL ALLOGRAFTINJURY A HISTORICALPERSPECTIVE

ldquoThose Who Cannot Remember thePast Are Condemned to Repeat Itrdquo2

It is instructive and sobering to note thatmuch research in chronic renal allograftinjury over the past 30 years involvedplausible hypotheses subsequentlyproven to be largely incorrect In the1980s several studies showed that thepatients who experienced an early acutecellular rejection (ACR) episode had lessfavorable long-term (usually 5-year)graft survival than those who remainedrejection-free3ndash5 Thus the concept thatlowering ACR rates would improvelong-term graft survival became widelyaccepted in kidney transplantationstimulating the development of new im-munosuppressants Indeed ACR re-mains an accepted end point for clinicaltrials by the Food and Drug Administra-tion (FDA) today However when newerprotocols lowered ACR rates routinely to10 in the first year late graft lossrates did not change1

Published online ahead of print Publication dateavailable at wwwjasnorg

Correspondence Dr Mark D Stegall Mayo Clinic200 SW First Street Rochester MN 55905 E-mailstegallmarkmayoedu

Copyright copy 2015 by the American Society ofNephrology

20 ISSN 1046-66732601-20 J Am Soc Nephrol 26 20ndash29 2015

In the1990s asmoredetailedhistologicstudies were conducted a hypothesisemerged that progressive fibrosis andvascular injury (termed chronic allograftnephropathy [CAN])were themajor causeof graft loss6 One report from Australiastudied 120 patients 119 of whom wererecipients of bladder-drained simulta-neous pancreas kidney transplants main-tained on cyclosporinazathioprine-basedimmunosuppression7 In surveillancebiopsies obtained at 5 years after transplan-tation 66 of patients showed moderate-to-severe interstitial fibrosis (ie Banffcriteria lesions moderate [ci2]=26ndash

50 of the cortical interstitium is fibroticsevere (ci3)50 of the cortical intersti-tium is fibrotic) Because calcineurin in-hibitors (CNIs) such as cyclosporinwere known to cause fibrosis in kidneysit was hypothesized that CAN was largelycaused by CNI nephrotoxicity This con-cept that chronic CNI nephrotoxicitywas a major contributor to chronic graftloss was widely embraced by the trans-plant community89

Multiple ensuing studies tested thehypothesis that minimization or avoid-

ance of CNI-based therapy could reducefibrosis and consequently improve long-termallograft survivalMost studieswererelatively short term with preservationof renal function (GFR)mdashbelieved to bepredictive of ultimate graft survivalmdashused as a surrogate end point Althoughsome single-center studies suggestedthat total avoidance of CNIs was safeand associated with better renal functionover time1011 other trials showed increasedACR in the patients on CNI-sparing andCNI-free therapies and minimal if anyimprovements in eGFR12ndash14 The effecton GFR tended to be particularly limitedwhen the CNIused was tacrolimus ratherthan cyclosporin15 For example theSymphony Study with over 1600 subjectswith 12 months of follow-up documen-ted a tacrolimus-based regimen to be as-sociated with less rejection less fibrosisand better renal function than either cy-closporin or CNI-free sirolimus-basedtherapy15

A major problem with the CNI neph-rotoxicityhypothesis is thatCNI-associatedhistologic lesions are relatively nonspe-cific and the diagnosis is commonly one

of exclusion made in patients with dys-function and no other discernable histo-logic diagnosis16 Ironically one groupsuggested that lesions commonly associ-ated with CNI nephrotoxicity were morefrequent in recipients who were on lowerdoses of the agent or nonadherent to ther-apy17 Currently there seems to be emerg-ing consensus that CNIs play little role ingraft loss early (5 years) after transplan-tation andCNIuse remains ubiquitous inrenal transplantationHowever the role ofCNI toxicity at later time points continuesto be debated including whether nephro-toxicity is primary or merely exacerbatesother mechanisms of injury

The CTLA4Ig fusion protein belata-ceptwas approvedby theFDAas part of aCNI-free regimen It has been shown toresult in more ACR but better renalfunction and less CAN at 1 and 3 yearscompared with a cyclosporin-based reg-imen18 Long-term outcomes of patientstreated with belatacept are not yet avail-able and it will be interesting to see ifthese early improvements in renal func-tion translate into improvements in graftsurvival

BROADENING THE CONCEPT OFCHRONIC RENAL ALLOGRAFTINJURY

In recent years a broader viewof chronicrenal allograft injury has emerged on thebasis of biopsy data from several largestudies of solitary kidney transplants(arguably a more appropriate studypopulation than bladder-drained simul-taneous pancreas kidney recipients)These studies have used two differentapproaches to investigate the causes ofchronic injurymdashone approach on thebasis of surveillance biopsies in wellfunctioning kidneys and one approachon the basis of biopsies for cause in kid-neys with dysfunction

The conclusions reached by these stud-ies may at first glance seem somewhatdifferent however we believe that theseapproaches are complementary and needto be reconciled if we are to have acomplete picture of chronic graft injuryLongitudinal surveillance biopsy data to

Figure 1 Rates of late renal allograft loss have remained constant (A) KaplanndashMeier cu-mulative graft failure and (B) death-censored graft failure by year of first deceased SCDtransplants from transplant years 1989ndash2008 Reprinted from ref 1 with permission

J Am Soc Nephrol 26 20ndash29 2015 Chronic Renal Allograft Injury 21

wwwjasnorg BRIEF REVIEW

datehave focusedmore intenselyoneventsin the first 5 years after transplantationData from this time frame suggest that notall grafts experience chronic injury andthat in those that do there are severaldifferent causes19 (Figure 2) In contrastbiopsy-for-cause studies tend to includemore late biopsies Donor-specific allo-antibody (DSA) seems to be a morecommon cause of graft loss during thislater time frame but inflammation alsomay continue to play a role Taken to-gether these studies identify a more co-herent model of chronic renal allograftinjury injury is not ubiquitous (evenwith CNI-based therapy) and there aredistinct causes of injury with importancethat varies at different times after trans-plantation

Graft Injury in the First Few YearsSubclinical Inflammation andRecurrent DiseaseThese more recent surveillance biopsystudies suggested that not all renal allo-grafts show evidence of significant injuryin thefirst fewyears after transplantationIn a report of 447 surveillance biopsies at1 and 5 years post-transplant the MayoClinic groupstudied recipientsof solitarykidney transplants performed between1998 and 2004 on tacrolimus-based im-munosuppression20 Moderate-to-severeinterstitial fibrosis was uncommon inboth 1- (13) and 5-year (17) biopsies

and rates were much lower than the 66incidence at 5 years described in the earlierAustralian study7 Also although mild fi-brosis (for example involving 25 ofthe interstitium) was relatively common(a 37 prevalence at 1 year) in the MayoClinic study it rarely progressed to moresevere formsby 5 years In factmany renalallografts (including those originating inboth LDs and deceased donors) showedrelatively normal histology at both 1 and 5years after transplantation In a subsequentanalysis of this cohort renal function re-mained stable or improved between 1and 5 years in 60 of recipients if the1-year biopsy was normal21 This con-cept was further supported by a studythat showed that the majority of renalallografts in this cohort with good

function at 1 year showed stable or in-creased renal function at 5 years aftertransplantation whereas only a subsetshows declining function (Figure 2)

The possible causes of graft loss inthese patients were examined in detailand found to be associated with severaldistinct post-transplant conditions in-cluding recurrent disease infectionmalignancy polyoma virus associatednephropathy and surprisingly ACR Im-portantly chronic antibody-associatedinjury (transplant glomerulopathy) andcalcineurin-inhibitor nephrotoxicityseemed to be uncommon causes of graftloss during the first 5 years after trans-plantation (Figure 3)

Surveillance biopsy studies have alsosuggested an association between intra-graft inflammation which affects15of renal allografts at 1 year and the de-velopment of interstitial fibrosis andorgraft loss22ndash27 It is unclear if subclinicalinflammation represents cell-mediatedalloimmunity against the allograft (it of-ten is not severe enough to meet Banffcriteria for ACR) or other processesincluding a nonspecific response toother forms of injury In both histologicand gene expression studies grafts withsubclinical inflammation seem qualita-tively if not quantitatively similar tografts with clinical ACR2627 One studysuggested a higher rate of transplant glo-merulopathy in grafts with prior sub-clinical inflammation28 Thus theremay be a link between the cellular al-loimmune response and the develop-ment of DSA

If subclinical inflammation early aftertransplantation truly represents a failureof conventional immunosuppression tocontrol the alloimmune response thentherapeutic trials aimed to prevent orreverse this process (rather than mini-mization of immunosuppression) mightbe a path to improving long-term graftsurvival in this subset of patients

Recurrence of native kidney diseasehas been a recognized cause of renalallograft loss for decades but early sur-veillance biopsy studies indicate that itseffect on long-term outcomes may havebeen underemphasized19 Althoughearly severe recurrence of primary

Figure 2 Changes in renal function after kidney transplantation MDRD Modification ofDiet in Renal Disease Reprinted from ref 21 with permission T12 1 year TLast Time oflast follow-up (mean 65 years) Q quintile patients were divided into quintiles based ontheir change in GFR over time

Figure 3 Causes of graft loss after kidneytransplantation on the basis of surveillancebiopsies Reprinted from ref 19 with per-mission

22 Journal of the American Society of Nephrology J Am Soc Nephrol 26 20ndash29 2015


FSGS and primary oxalosis are welldocumented surveillance biopsy studieshave shown a high incidence of recur-rence of several glomerular diseasesFor example membranoproliferativeGN has a high rate of recurrence aftertransplantation (42 in one protocol bi-opsy series) with graft loss commonlyoccurring in the first few years29 IgA ne-phropathy also commonly recurs butdoes not often progress rapidly to graftfailure19 In relatively young transplantrecipients recurrent disease may be anespecially vexing problem given the fre-quency of glomerular disease causingESRD and their lengthy projected post-transplant survival Obviously recurrentdisease is a heterogeneous problem butadvances in recognition and therapyhave the potential to contribute to betterlong-term graft survival

Late Graft Injury The Emergence ofAlloantibodyBiopsies performed to evaluate new-onsetgraft dysfunction or proteinuria5 yearsafter transplantation consistently indi-cate a major role for antibody-mediatedlate graft injury In the Deterioration ofKidney Allograft Function (DeKAF) Tri-al subjects underwent for-cause biopsies75660 years post-transplant Patientswith DSA C4d or both were at substan-tial risk of graft failure over 2 years post-biopsy (Figure 4) The severity of clinicalinjury correlated with the intensity of an-tibody response30

Another recent large biopsy-for-causestudy reached similar conclusions TheEdmonton group studied 315 allografts60 of which failed As shown below theincidence of dysfunction caused by an-tibody-mediated rejection increasedover timemdashespecially beyond 5 years af-ter transplantation (Figure 5)31

Although an in-depth review of therole of DSA in late graft failure is beyondthe scope of this review several impor-tant aspects of this issue are importantto our discussion here Hamburgeret al32 noted a relationship between al-loantibody and chronic rejectionalmost a half century ago Howeverthe development of several new techni-ques including improved methods to

identify DSA (single-antigen bead as-says)33 improved histologic assessment(C4d staining and the recognition of his-tologic changes such as glomerulopathyand microvascular inflammation)3435

and specific gene expression profileshas enabled investigators to clearly estab-lish its role in chronic injury3637However

the exact mechanisms of chronic anti-body-associated injury remain some-what unclear The recognition of C4d2antibody-mediated injury suggests thatcomplement independent processessuch as microvascular inflammation mayplay a major role in chronic antibody-mediated injury

Figure 4 Relationship between DSA and C4d+ staining and graft survival in biopsies forcause Reprinted from ref 30 with permission

Figure 5 Causes of graft loss over time in biopsies for cause Reprinted from ref 31 withpermission



Several recent longitudinal studieshave examined the role of de novo DSA(dnDSA) in late graft loss in more de-tail38ndash40 In previously unsensitized re-cipients prevalence of dnDSA at 1 yearis documented as approximately 11with an increase to around 30 at 10years The actual 3-year death-censoredgraft loss after dnDSA was 24 Wiebeet al39 documented dnDSA in 15 oflow-risk patients at 4663 years post-transplant 10-year graft survival was57 in those with dnDSA and 96 inthose without dnDSA

Beyond DSA subclinical inflam-mation also seems to be an importantpredictor of late graft loss in biopsy-for-cause studies4142 However the inflam-mation seems to be slightly differentfrom that seen in surveillance biopsiesand further illustrates yet another im-portant difference between these two bi-opsy approaches Not only are biopsiesfor cause obtained later they are ob-tained from grafts with dysfunctionsthat commonly have more chronic dam-age (fibrosis and tubular atrophy for ex-ample) than the average well functioningrenal allograft In these biopsies inflam-mation in areas of fibrosis has beenshown to be relatively common and animportant predictor of subsequent graftloss in biopsy-for-cause studies For ex-ample analysis of the DeKAF cohortsuggested that relatively intense levelsof inflammation in areas of fibrosis (forexample a score of 3=50 involvement)were associated with an increased risk ofgraft loss even when adjusted for theamount of fibrosis42 Inflammationwith such advanced fibrosis is less com-mon in surveillance biopsies and it isunclear if this result represents a differ-ent pathologic process or a continuumof chronic injury

Certainly the biopsy data summa-rized here underscore the deficienciesassociated with using histology alone toclassify chronic injury processes Geno-mic andproteomicmethodologiesmightenhance diagnostic accuracy of biopsiesand provide new insight intomechanismsof damage4344 However the prepon-derance of existing evidence supportsalloimmune mechanisms as of profound

significance in causing late allograftfailure

CONTRIBUTING FACTORS

In addition to the major factors linked tolate graft failure there are likelyothers thatplay a more secondary role in pathogen-esis either enabling or exacerbatingchronic injury For example the effect ofearly post-transplant events (ischemiareperfusion injury and innate immunity)on chronic injury remains unclear but itmay set the stage for other adverse eventsAllograft quality and donor age are com-monly factors associated with graft loss inmultivariate analyses and thus may affectthe ultimate outcome of subsequent al-loimmune injury4546 Other factors suchas long-standing hypertension and diabe-tes also may contribute to graft injurywith the potential to modify the efficacyof any therapeutic intervention Recentlyone group suggested a connection be-tween the microbiome and chronic in-jury47 Finally although its importancewas recognized early recent studies havere-emphasized the importance of nonad-herence as either a causative or contribut-ing factor for some cases of late failure

When viewed in perspective thesestudies indicate that there are multiplecauses of late renal allograft loss It is aremarkable calculus in which these het-erogeneous pathologic influences oc-curring with varying frequency and atdifferent time points result in an almostlinear rate of graft loss over many years

CLINICAL TRIAL DESIGN ANDSURROGATE END POINTS

This broadened view of chronic injuryhas important implications for the ra-tional design of clinical trials to preventor treat chronic renal allograft injuryTwo areas that deserve specific mentionare the inclusion criteria and the studyend points

Because most patients do not haveprogressive dysfunction most will notrequire alteration of immunosuppres-sion beyond current standards Including

patients who would do well in a studyaimed to improve graft survival is un-necessary It increases costs and detractsfrom the ability to show an effect of theintervention Thus it is unlikely that asingle novel therapeutic interventionparticularly if instituted at the time oftransplantation will show improvementsin long-term graft survival Progress willinvolve the enrollment of patients with aspecific cause of graft loss at some pointafter transplantation Although this ap-proach risks intervening too latewhen theinjury process may not be easily reversedor graft damage is permanent it shouldenable design of more feasible clinicaltrials Defining inclusion criteria and thetiming of intervention are two of themajor challenges facing this area alongwith relatively nonspecific inclusion cri-teria such as fibrosis or inflammationrisk including a heterogeneous group ofpatients who may not respond equally tothe therapeutic intervention

However even in a subset of high-riskrecipients with a specific identifiablecause of injury any study of chronicrenal allograft injury still will take manyyears to show efficacy This brings us tothe important role of surrogate endpoints in the study of chronic renalallograft injury

In the context of long-term studies asurrogate endpoint is used as the study endpoint rather than graft loss The primarybenefit of a surrogate marker is to decreasethe time interval between therapeutic in-terventionandability todetermine efficacyIdeally improvement in a surrogatemarkerwould lead to improvement in subsequentgraft survival Unfortunately the correla-tion between improvement in a surrogatemarker and improvement in graft survivalis always less than perfect In many in-stances the correlation can be quite poorThus we contend that surrogate mark-ers must still be considered interim endpoints The final end point remains graftsurvival

Surrogate end points such as renalfunction DSA proteinuria and grafthistology have been used in renal trans-plant trials for many years and all havebeen shown to have some correlationwith late transplant outcomes (Table 1)



The past several years have seen an ex-plosion in the number of biomarkersin renal transplantation Although anyfactor is technically a biomarker moststudies have focused on specificmolecules(cytokines chemokines cell surfacemolecules gene expression signaturesmicroRNA etc) studied in urine bloodor tissue4248ndash59Many studies of biomark-ers have aimed to detect surrogates forACR using either a single biomarker or aset of biomarkers Other studies have fo-cused on markers of delayed graft func-tion or progression of native renal diseaseA few biomarker studies have focused onchronic injury (Table 2)

Several recent reviews have examinedbiomarkers in detail4248ndash50 and we willconfine our discussion to relatively fewwith a special emphasis on issues relatedto the study of chronic injury

As we describe here the problemwith many of the biomarkers that havebeen suggested is that they are relativelynonspecific and thus may be problem-atic end points for clinical trials aimedat treating a specific cause of late graftloss

Renal FunctionImprovement in renal function at earlytime points (for example at 1 year) is acommonly used surrogate end point forimproved graft survival Beyond theongoing debate regarding the optimalapproach for determining GFR and theneed for accurate serial measurementsthere may be pitfalls to this approach topreventing graft failure Most importantis the fact that the correlation between

early renal function and subsequentgraft survival is relatively poor Al-though it is true that a low GFR at 1year is associated with a higher rate ofgraft loss its ability to predict graftfailure is relatively limited60 Indeedmost patients with graft loss between 1and 5 years have normal renal functionat 1 year21 There also is little evidencethat improving early GFR actually im-proves graft survival Declining GFR(DGFR) over time may be more predic-tive of late allograft failure andtherefore a better surrogate end point

HistologyHistologic changes such as transplantglomerulopathy or subclinical inflam-mation are moderately good predictorsof subsequent graft loss23 Howevereven if transplant glomerulopathy couldbe both accurately quantified and asso-ciated with a 50 incidence of graft losswithin 5 years of diagnosis very largenumbers of subjects would be necessaryto show efficacy Studies using subclinicalinflammation at 1 year would require evenlarger numbers Histologic markers alsoare invasive costly and prone to errorsin sampling quantitation and interpre-tation It is also not certain whether sur-veillance biopsies or biopsies for causeoffer the best chance for identification ofhigh-risk patients at a time point whenchronic injury is reversible (likely morecommon in surveillance biopsies and lesscommon in for-cause biopsies) Stillusing histologic changes as inclusioncriteria or their reversal or stabilizationas an end point would seem a fertile area

for future study of interventions inchronic injury

DSADSAseems tobea relatively goodsurrogatemarker in studies of chronic antibody-mediated injury It is relativelynoninvasiveand thus can be performed sequentiallyin the same patient allowing for pre- andpost-treatment assessment with a primaryendpointofadecrease inDSAoreven totaldisappearance of DSA in the treatmentgroup Alternatively preventing dnDSAaltogether might be an appropriate endpoint in a broader study of newly trans-planted patients

However there are several problemseven with this relatively objective mea-sure First DSA has only a moderatelyhigh correlation with graft loss As de-scribed above the actual 3-year death-censored graft loss after dnDSAwas 24Thus even studies with DSA as a surro-gate end pointwill require relatively largenumbers of patients followed for manyyears to show improvement in graftsurvival Second there is no consensuson how to measure DSA For exampleLABScreen and other solid-phase assaysare not licensed by the FDA for measur-ing different levels of DSAmdashonly theirpresence or absence There also can besignificant interlaboratory variability inthese tests Recently C1q-binding anti-bodies have been suggested to correlatebetter with both acute and chronic anti-body-mediated injury and thus may be abetter surrogate marker6162 Finally se-rum DSA may not always correspondwith tissue injury In the DeKAF Study

Table 1 Surrogate biomarkers in kidney transplantation Surrogate end points shown to correlate with post-transplantoutcome

Sample SourceMeasurement Strengths Weaknesses

SerumRenal function Serial measurements provides insight into

current graft functionOften involves surrogates (ie serum creatinine)

to estimate functionDSA (HLA) Early marker of antibody injury Uncommon early post-transplant no effective

treatmentUrineProteinuria Shown to be associated with currentfuture

graft statusResults can be influenced by many factors (infection

recurrent disease etc)TissueGraft histology (protocol and

biopsy for cause)Visual evidence of what is happening in the graft Invasive costly variable samplinginterpretation



for example patients whose biopsiesshowed C4d+ had the same risk of graftfailure with or without DSA This resultcould reflect the effect of non-HLA an-tibody or low levels of circulating alloan-tibody which are difficult to distinguishat present

Gene Expression SignaturesAs mentioned above relatively few bio-markers have been identified as beingrelated to chronic injury and it is unclearwhich approach will emerge as beingmost important The most widely stud-ied biomarker has been gene expressionsignatures in allograft biopsies associatedwith chronic antibody-mediated injurywhich were described by the Edmontongroup63 Using an Affymetrix gene chipplatform this grouphas identified a groupof genes associatedwith antibody-mediatedrejection (primarily genes related to nat-ural killer cells and other microvascularinflammation)63 This test set of geneswas validated in a separate group of bi-opsies and thus has been shown tobe reproducible64 This group has sug-gested that gene expression enhances thediagnosis of AMR when used in con-junction with other factors includinghistology65 As we gain more experiencein this area changes in gene expressionsignatures or other biomarkers will likelyemerge as important surrogate end pointsfor chronic injury intervention trials

A PATH FORWARD

The rapid advance in transplant therapeu-tics that characterized the last quarterof the

20th century has slowed significantly ThistrendrecognizedinrecentFDAworkshopshas become a major concern to the trans-plantcommunityInitsrecentCall toAction

Table 2 Additional biomarkers proposed to correlate with post-transplant outcome

IndicationMarker(s) Sample Source Laboratory Platform Specimen Time and Finding Refs

Chronic allograft damageACY-1 Serum ELISA May distinguish patients with delayed graft

function at highlow risk for future graft loss51

B2M Serum Multiple Baseline strongly associated with subsequentdeathgraft loss

52

CXCL-9 Urine ELISA Low 6-mo value associated with stable eGFRto 24 mo multicenter validation

53

CCL-2 Urine ELISA 6-Mo measure associated with future graft loss 54Chronic antibody-mediated rejectionGene expression Biopsy Microarray Early and late biopsies 63ndash65MicroRNA 142ndash5p Blood MicroRNA TaqMan assays Increased detection in the blood at time

of biopsy-proven chronic antibodymediated rejection

55

Tribbles-1 Blood RT-PCR Increased expression at time of biopsy-provenchronic antibody mediated rejection withhigh specificity and sensitivity versus othertypes of late allograft injury

56

Table 3 Proposed Clinical Trial Design for new therapy to prevent chronic renalallograft injury

Aim To demonstrate that bortezomib prevents progression of chronic antibody mediateddamage1 Patient Selection Identify patients at high risk for graft lost

c 12ndash60 months after kidney transplantationc Serum donor-specific alloantibody with mean fluorescence index (MFI) 2000(on 2 sequential measurements within 1ndash3 months of each other) No DSA at the time oftransplant (ie de novo DSA)

c Renal allograft biopsy at the time of enrollment to demonstrate the absence of moderate-to-severe transplant glomerulopathy (cg score 1) and an absence of acute cellularrejection grade Ia or higher (Banff)

c Randomize to receive bortezomib monotherapy vs placebo (blinded)2 Surrogate Endpoint for InitialTrial

Primary endpointc Reduction in MFI level 1 year after treatment (paired t test with each patient serving astheir own control)

Secondary endpointsc Lack of progression of cg score on 1 year follow-up biopsyc Lack of progression of peritubular capillaritis score on 1 year follow-up biopsyc Lack of decline in renal function 1 year after treatment

3 Initial approval based on surrogate endpointc If primary endpoint is reached (ie drug actually reduces DSA) then the drug will be givenapproval by regulatory agencies for the treatment of chronic antibody mediated injury

4 Final Approvalc Long-term follow-up to demonstrate that the therapy improves long-term graft survivalin the study cohort Likely this would be 5 years or more after initial approval

The following is an example of the type of protocol that meets the criteria that we describe in the text 1)identify a patient populationwith a specific risk factor for late graft loss (de novoDSA) 2) utilize a surrogateendpoint for initial regulatory approval and 3) long-term follow-up to demonstrate that the therapy im-proves graft survival



the American Society of Transplantationhighlighted the issue by noting that addi-tional advances are unlikely without novelclinical trial designs66 This finding is espe-cially true for trials in therapy for the pre-vention of chronic renal allograft injury

Table 3 outlines an example of the typeof protocol that would address the uniqueproblems facing studies of chronic injuryThis protocol would enroll patients witha clearly defined cause of graft injury thatplaces themathigh risk for subsequent graftloss (in this case dnDSA)Theprotocol usesa surrogate marker that is closely relatedto the underlying pathologic processmdashthereduction in DSA or prevention of trans-plant glomerulopathy Achieving this pri-mary end point would be sufficient toobtain interim or expedited drug approvalfrom agencies such as the FDA (for ex-ample Subpart H)67 The demonstrationof improved graft survival would lead tofinal approval at some later time point

Similar studies could be designed tostudy recurrent disease polyoma virusassociated nephropathy or even non-adherence Studies like these could beused to validate any biomarkers as sur-rogates for graft loss including intragraftgene expression or other biomarkersAlthough using this approach does notguarantee success it is likely to yieldimportant knowledge related to themechanisms of antibody-mediated in-jury regardless of the outcome

We are optimistic regarding our abilityto improve long-term renal allograft sur-vival Our knowledge of late graft failurehas advanced significantly in the last de-cade and is sufficient to generate severalnew testable hypotheses We like ourpredecessors may be at risk of launchingtherapeutic trials on the basis of faultyparadigms However delaying new trialsuntil each nuance is carefully explainedandcanbeaddressedwill serveneitherourpatients nor our profession Advances willcome only if all interested parties adoptnewinvestigativeapproaches to improvingkidney transplant survival

DISCLOSURESThe authors have received research contracts

from Millennium and Alexion

REFERENCES

1 LambKE Lodhi SMeier-KriescheH-U Long-term renal allograft survival in the UnitedStates A critical reappraisalAm J Transplant

11 450ndash462 20112 Santayana G The Life of Reason Vol 1 Am-

herst New York Prometheus Books 19983 Kasiske BL Kalil RS Lee HS Rao KV Histo-

pathologic findings associated with achronic progressive decline in renal allograftfunction Kidney Int 40 514ndash524 1991

4 Ferguson R Acute rejection episodesmdashbestpredictor of long-term primary cadaveric re-nal transplant survival Clin Transplant 8328ndash331 1994

5 Tantravahi J Womer KL Kaplan B Why hasnrsquoteliminating acute rejection improved graftsurvival Annu Rev Med 58 369ndash385 2007

6 Myers BD Ross J Newton L Luetscher JPerlroth M Cyclosporine-associated chronicnephropathyNEnglJMed311699ndash7051984

7 Nankivell BJ Borrows RJ Fung CLOrsquoConnell PJ Allen RD Chapman JR Thenatural history of chronic allograft nephrop-athy N Engl J Med 349 2326ndash2333 2003

8 Nankivell BJ Borrows RJ Fung CLOrsquoConnell PJ Chapman JR Allen RD Calci-neurin inhibitor nephrotoxicity Longitudinalassessment by protocol histology Trans-

plantation 78 557ndash565 20049 Salvadori M Bertoni E Is it time to give up

with calcineurin inhibitors in kidney trans-plantationWorld J Transplant 3 7ndash25 2013

10 Gonwa TA Hricik DE Brinker K Grinyo JMSchena FP Sirolimus Renal Function StudyGroup Improved renal function in sirolimus-treated renal transplant patients after earlycyclosporine elimination Transplantation 741560ndash1567 2002

11 Flechner SM Goldfarb D Solez K Modlin CSMastroianni B Savas K Babineau D Kurian SSalomon D Novick AC Cook DJ Kidneytransplantation with sirolimus and mycopheno-late mofetil-based immunosuppression 5-yearresults of a randomized prospective trial com-pared to calcineurin inhibitor drugs Trans-plantation 83 883ndash892 2007

12 Larson TS Dean PG Stegall MD Griffin MDTextor SC Schwab TR Gloor JM Cosio FGLundWJKremersWKNybergSL IshitaniMBPrieto M Velosa JA Complete avoidance ofcalcineurin inhibitors in renal transplantationA randomized trial comparing sirolimus andtacrolimus Am J Transplant 6 514ndash522 2006

13 Glotz D Charpentier B Abramovicz D LangP Rostaing L Rifle G Vanrenterghem YBerthoux F Bourbigot B Delahousse MChalopin JM Cassuto E Lefranccedilois N Thy-moglobulin induction and sirolimus versustacrolimus in kidney transplant recipientsreceiving mycophenolate mofetil and ste-roids Transplantation 89 1511ndash1517 2010

14 Flechner SM GlydaM Cockfield S Grinyoacute JLegendre C Russ G Steinberg S Wissing

KM Tai SS The ORION study Comparisonof two sirolimus-based regimens versus ta-crolimus and mycophenolate mofetil in renalallograft recipients Am J Transplant 111633ndash1644 2011

15 Ekberg H Tedesco-Silva H Demirbas AVitko S Nashan B Gurkan A Margreiter RHugo C Grinyo JM Frei U Vanrenerghem YDaloze P Halloran PF ELITE-SymphonyStudy Reduced exposure to calcineurin in-hibitors in renal transplantation N Engl JMed 357 2562ndash2575 2007

16 Matas AJ Leduc R Rush D Cecka JMConnett J Fieberg A Halloran P HunsickerL Cosio F Grande JMannon R GourishankarS Gaston R Kasiske B Histopathologic clus-ters differentiate subgroups within the non-specific diagnoses of CAN or CR Preliminarydata from the DeKAF study Am J Transplant10 315ndash323 2010

17 Lerut E KuypersDR Verbeken E Cleutjens JVlaminck H Vanrenterghem Y Van DammeB Acute rejection in non-compliant renal al-lograft recipients A distinct morphologyClin Transplant 21 344ndash351 2007

18 Vincenti F Charpentier B Vanrenterghem YRostaing L Bresnahan B Darji P Massari PMondragon-Ramirez GA Agarwal M DiRusso G Lin CS Garg P Larsen CP A phaseIII study of belatacept-based immunosup-pression regimens versus cyclosporine inrenal transplant recipients (BENEFIT study)Am J Transplant 10 535ndash546 2010

19 El-Zoghby ZM Stegall MD Lager DJKremers WK Amer H Gloor JM Cosio FGIdentifying specific causes of kidney allograftloss Am J Transplant 9 527ndash535 2009

20 Stegall MD Park WD Larson TS Gloor JMCornell LD Sethi S Dean PG PrietoM AmerH Textor S Schwab T Cosio FG The his-tology of solitary renal allografts at 1 and 5years after transplantation Am J Transplant11 698ndash707 2011

21 Park WD Larson TS Griffin MD Stegall MDIdentification and characterization of kidneytransplants with good glomerular filtrationrate at 1 year but subsequent progressiveloss of renal function Transplantation 94931ndash939 2012

22 Shishido S Asanuma H Nakai H Mori YSatoh H Kamimaki I Hataya H Ikeda MHonda M Hasegawa A The impact of re-peated subclinical acute rejection on theprogression of chronic allograft nephropa-thy J Am Soc Nephrol 14 1046ndash10522003

23 Cosio FG Grande JP Wadei H Larson TSGriffin MD Stegall MD Predicting sub-sequent decline in kidney allograft functionfrom early surveillance biopsies Am JTransplant 5 2464ndash2472 2005

24 Moreso F Ibernon M Gomagrave M Carrera MFulladosa X Hueso M Gil-Vernet S CruzadoJM Torras J Grinyoacute JM Seroacuten D Subclinicalrejection associated with chronic allograftnephropathy in protocol biopsies as a risk



factor for late graft loss Am J Transplant 6747ndash752 2006

25 Heilman RL Khamash HA Smith MLChakkera HA Moss AA Reddy KS Delayedallograft inflammation following alemtuzu-mab induction for kidney transplantationClin Transplant 27 772ndash780 2013

26 Naesens M Kuypers DR De Vusser KVanrenterghem Y Evenepoel P Claes KBammens B Meijers B Lerut E Chronic his-tological damage in early indication biopsies isan independent risk factor for late renal allo-graft failure Am J Transplant 13 86ndash99 2013

27 Park WD Griffin MD Cornell LD Cosio FGStegall MD Fibrosis with inflammation at oneyear predicts transplant functional decline JAm Soc Nephrol 21 1987ndash1997 2010

28 El Ters M Grande JP Keddis MT Rodrigo EChopra B Dean PG Stegall MD Cosio FGKidney allograft survival after acute rejectionthe value of follow-up biopsies Am J Trans-plant 13 2334ndash2341 2013

29 RodriguezEFCosioFGNasrSHSethi S FidlerME Stegall MD Grande JP Fervenza FCCornell LD The pathology and clinical featuresof early recurrent membranous glomerulone-phritis Am J Transplant 12 1029ndash1038 2012

30 Gaston RS Cecka JM Kasiske BL FiebergAM Leduc R Cosio FC Gourishankar SGrande J Halloran P Hunsicker LMannonRRush D Matas AJ Evidence for antibody-mediated injury as a major determinant oflate kidney allograft failure Transplantation90 68ndash74 2010

31 Sellareacutes J de FreitasDGMengelM Reeve JEinecke G Sis B Hidalgo LG Famulski KMatas A Halloran PF Understanding thecauses of kidney transplant failure Thedominant role of antibody-mediated re-jection and nonadherence Am J Transplant12 388ndash399 2012

32 Hamburger J Crosnier J Dormont J BachJF Renal Transplantation Theory and Prac-tice Baltimore MD The Williams and WilkinsCo 1972

33 EverlyMJTerasaki PIMonitoringand treatingposttransplant human leukocyte antigen anti-bodies Hum Immunol 70 655ndash659 2009

34 Feucht HE Complement C4d in graftcapillaries mdash the missing link in the recog-nition of humoral alloreactivity Am J Trans-plant 3 646ndash652 2003

35 Loupy A Suberbielle-Boissel C Hill GSLefaucheur C Anglicheau D Zuber JMartinez F Thervet E Meacutejean A Charron DDuong van Huyen JP Bruneval P LegendreC Nochy D Outcome of subclinical antibody-mediated rejection in kidney transplant recipi-ents with preformeddonor-specific antibodiesAm J Transplant 9 2561ndash2570 2009

36 Sellareacutes J Reeve J Loupy A Mengel M SisB Skene A de Freitas DG Kreepala CHidalgo LG Famulski KS Halloran PF Mo-lecular diagnosis of antibody-mediated re-jection in human kidney transplants Am JTransplant 13 971ndash983 2013

37 Stegall MD Raghavaiah S Gloor JM The (re)emergence of B cells in organ transplantationCurr Opin Organ Transplant 15 451ndash4552010

38 Hourmant M Cesbron-Gautier A Terasaki PIMizutani K Moreau A Meurette A Dantal JGiral M Blancho G Cantarovich D Karam GFollea G Soulillou JP Bignon JD Frequencyand clinical implications of development ofdonor-specific and non-donor-specific HLAantibodies after kidney transplantation J AmSoc Nephrol 16 2804ndash2812 2005

39 Wiebe C Gibson IW Blydt-Hansen TDKarpinskiMHoJ Storsley LJGoldbergA BirkPE Rush DN Nickerson PW Evolution andclinical pathologic correlations of de novo do-nor-specific HLA antibody post kidney trans-plant Am J Transplant 12 1157ndash1167 2012

40 Everly MJ Rebellato LM Haisch CE OzawaM Parker K Briley KP Catrou PG Bolin PKendrick WT Kendrick SA Harland RCTerasaki PI Incidence and impact of de novodonor-specific alloantibody in primary renalallografts Transplantation 95 410ndash4172013

41 Mengel M Reeve J Bunnag S Einecke GJhangriGS Sis B Famulski KGuembes-HidalgoL Halloran PF Scoring total inflammation issuperior to the current Banff inflammationscore in predicting outcome and the degreeof molecular disturbance in renal allograftsAm J Transplant 9 1859ndash1867 2009

42 Mannon RB Matas AJ Grande J Leduc RConnett J Kasiske B Cecka JM Gaston RSCosioFGourishankarSHalloranPFHunsickerL Rush D DeKAF Investigators Inflamma-tion in areas of tubular atrophy in kidneyallograft biopsies A potent predictor ofallograft failure Am J Transplant 10 2066ndash2073 2010

43 Sis B Jhangri GS Bunnag S Allanach KKaplan B Halloran PF Endothelial gene ex-pression in kidney transplants with alloanti-body indicates antibody-mediated damagedespite lack of C4d stainingAm JTransplant9 2312ndash2323 2009

44 Halloran PF Reeve JP Pereira AB HidalgoLG Famulski KS Antibody-mediated re-jection T cell-mediated rejection and theinjury-repair response New insights from theGenomeCanada studies of kidney transplantbiopsies Kidney Int 85 258ndash264 2014

45 Tasaki M Saito K Nakagawa Ikeda M ImaiN Narita I Takahashi K Effect of donor-recipient age difference on long-term graftsurvival in living kidney transplantation IntUrol Nephrol 46 1441ndash1446 2014

46 Lim WH Clayton P Wong G Campbell SBCohney S Russ GR Chadban SJ McDonaldSP Outcomes of kidney transplantation fromolder living donors Transplantation 95 106ndash113 2013

47 Cheng J Torkamani A Grover RK Jones TMRuiz DI Schork NJ Quigley MM Hall FWSalomon DR Lerner RA Ectopic B-cell clus-ters that infiltrate transplanted human

kidneys are clonal Proc Natl Acad Sci U S A108 5560ndash5565 2011

48 Roedder S Vitalone M Khatri P Sarwal MMBiomarkers in solid organ transplantationEstablishing personalized transplantationmedicine Genome Med 3 37 2011

49 Lo DJ Kaplan B Kirk AD Biomarkers forkidney transplant rejectionNat Rev Nephrol10 215ndash225 2014

50 Brunet M Cytokines as predictive bio-markers of alloreactivityClin Chim Acta 4131354ndash1358 2012

51 Welberry Smith MP Zougman A Cairns DAWilson M Wind T Wood SL Thompson DMessengerMPMooneyASelbyPJ LewingtonAJ Banks RE Serum aminoacylase-1 is a novelbiomarker with potential prognostic utility forlong-term outcome in patients with delayedgraft function following renal transplantationKidney Int 84 1214ndash1225 2013

52 Astor BC Muth B Kaufman DB Pirsch JDMichael Hofmann R Djamali A Serum b2-microglobulin at discharge predictsmortalityand graft loss following kidney trans-plantation Kidney Int 84 810ndash817 2013

53 Hricik DE Nickerson P Formica RN PoggioED RushDNewell KAGoebel J Gibson IWFairchild RL RiggsM Spain K IkleD BridgesND Heeger PS CTOT-01 consortium Mul-ticenter validation of urinary CXCL9 as a risk-stratifying biomarker for kidney transplantinjury Am J Transplant 13 2634ndash2644 2013

54 Ho J Wiebe C Rush DN Rigatto C StorsleyL Karpinski M Gao A Gibson IW NickersonPW Increased urinary CCL2 Cr ratio at 6months is associated with late renal allograftloss Transplantation 95 595ndash602 2013

55 Danger R Paul C Giral M Lavault A FoucherYDegauqueNPallierADurandMCastagnetS Duong Van Huyen JP Delahousse MRenaudin K Soulillou JP Brouard S Ex-pression of miR-142-5p in peripheral bloodmononuclear cells from renal transplant pa-tients with chronic antibody-mediated re-jection PLoS ONE 8 e60702 2013

56 Ashton-Chess J Giral M Mengel MRenaudin K Foucher Y GwinnerW Braud CDugast E Quillard T Thebault P ChiffoleauE Braudeau C Charreau B Soulillou JPBrouard S Tribbles-1 as a novel biomarker ofchronic antibody-mediated rejection J AmSoc Nephrol 19 1116ndash1127 2008

57 Li L Khatri P Sigdel TK Tran T Ying LVitalone MJ Chen A Hsieh S Dai H ZhangM Naesens M Zarkhin V Sansanwal P ChenRMindrinosM XiaoW BenfieldM EttengerRB Dharnidharka V Mathias R Portale AMcDonald R Harmon W Kershaw DVehaskari VM Kamil E Baluarte HJ WaradyB Davis R Butte AJ Salvatierra O SarwalMM A peripheral blood diagnostic test foracute rejection in renal transplantation Am JTransplant 12 2710ndash2718 2012

58 Jin ZK Tian PX Wang XZ Xue WJ Ding XMZheng J Ding CG Mao TC Duan WL Xi MKidney injurymolecule-1andosteopontinNew



markers for prediction of early kidney transplantrejectionMol Immunol 54 457ndash464 2013

59 Ramiacuterez-Sandoval JC Barrera-Chimal JSimancas PE Rojas-Montantildeo A Correa-RotterR Bobadilla NA Morales-Buenrostro LE Uri-nary neutrophil gelatinase-associated lipocalinpredicts graft loss after acute kidney injury inkidney transplant Biomarkers 19 63ndash69 2014

60 Kaplan B Schold J Meier-Kriesche H-U Poorpredictive value of serum creatinine for renal al-lograft lossAmJTransplant31560ndash15652003

61 Loupy A Lefaucheur C Vernerey D PruggerC Duong van Huyen JP Mooney NSuberbielle C Fremeaux-Bacchi V MejeanA Desgrandchamps F Anglicheau D NochyD Charron D Empana JP Delahousse MLegendre C Glotz D Hill GS Zeevi AJouven XN Complement-binding anti-HLAantibodies and kidney-allograft survival NEngl J Med 369 1215ndash1226 2013

62 Chen G Tyan DB C1q assay for the detectionof complement fixing antibody to HLA anti-gensMethods Mol Biol 1034 305ndash311 2013

63 Hidalgo LG Sis B Sellares J Campbell PMMengel M Einecke G Chang J Halloran PFNK cell transcripts and NK cells in kidneybiopsies from patients with donor-specificantibodies Evidence for NK cell involvementin antibody-mediated rejection Am JTransplant 10 1812ndash1822 2010

64 Halloran PF Pereira AB Chang J Matas APictonM De Freitas D Bromberg J SeroacutenDSellareacutes J Einecke G Reeve J Microarraydiagnosis of antibody-mediated rejection inkidney transplant biopsies An internationalprospective study (INTERCOM) Am JTransplant 13 2865ndash2874 2013

65 Loupy A Lefaucheru C VernereyD Chang JHidalgo LG Beauscart T Verine J Aubert ODubleumortier S Duong van Huyen JP

Jouven X Glotz D Legendre C Halloran PFMolecular microscopy strategy to improverisk stratification in early antibody-mediatedkidney allograft rejection [published onlineahead of print April 3 2014] J Am SocNephrol 101681ASN2013111149

66 A Call to Action reviving the pipeline oftherapeutic agent and device innovation intransplantation AST recommendations for amemo of understanding with Food and DrugAdministration to improve transplant therapies20xx Available at httpwwwmyastorgsitesdefaultfilespdfsfda_moucalltoaction_final_5_13_13_0pdf Accessed March 1 2014

67 Subpart H Accelerated approval for newdrugs for serious or life-threatening illnesses20xx Available at httpwwwaccessdatafdagovscriptscdrhcfdocscfcfrCFRSearchcfmCFRPart=314ampshowFR=1ampsubpartNode=21501148 Accessed March 1 2014



In the1990s asmoredetailedhistologicstudies were conducted a hypothesisemerged that progressive fibrosis andvascular injury (termed chronic allograftnephropathy [CAN])were themajor causeof graft loss6 One report from Australiastudied 120 patients 119 of whom wererecipients of bladder-drained simulta-neous pancreas kidney transplants main-tained on cyclosporinazathioprine-basedimmunosuppression7 In surveillancebiopsies obtained at 5 years after transplan-tation 66 of patients showed moderate-to-severe interstitial fibrosis (ie Banffcriteria lesions moderate [ci2]=26ndash

50 of the cortical interstitium is fibroticsevere (ci3)50 of the cortical intersti-tium is fibrotic) Because calcineurin in-hibitors (CNIs) such as cyclosporinwere known to cause fibrosis in kidneysit was hypothesized that CAN was largelycaused by CNI nephrotoxicity This con-cept that chronic CNI nephrotoxicitywas a major contributor to chronic graftloss was widely embraced by the trans-plant community89

Multiple ensuing studies tested thehypothesis that minimization or avoid-

ance of CNI-based therapy could reducefibrosis and consequently improve long-termallograft survivalMost studieswererelatively short term with preservationof renal function (GFR)mdashbelieved to bepredictive of ultimate graft survivalmdashused as a surrogate end point Althoughsome single-center studies suggestedthat total avoidance of CNIs was safeand associated with better renal functionover time1011 other trials showed increasedACR in the patients on CNI-sparing andCNI-free therapies and minimal if anyimprovements in eGFR12ndash14 The effecton GFR tended to be particularly limitedwhen the CNIused was tacrolimus ratherthan cyclosporin15 For example theSymphony Study with over 1600 subjectswith 12 months of follow-up documen-ted a tacrolimus-based regimen to be as-sociated with less rejection less fibrosisand better renal function than either cy-closporin or CNI-free sirolimus-basedtherapy15

A major problem with the CNI neph-rotoxicityhypothesis is thatCNI-associatedhistologic lesions are relatively nonspe-cific and the diagnosis is commonly one

of exclusion made in patients with dys-function and no other discernable histo-logic diagnosis16 Ironically one groupsuggested that lesions commonly associ-ated with CNI nephrotoxicity were morefrequent in recipients who were on lowerdoses of the agent or nonadherent to ther-apy17 Currently there seems to be emerg-ing consensus that CNIs play little role ingraft loss early (5 years) after transplan-tation andCNIuse remains ubiquitous inrenal transplantationHowever the role ofCNI toxicity at later time points continuesto be debated including whether nephro-toxicity is primary or merely exacerbatesother mechanisms of injury

The CTLA4Ig fusion protein belata-ceptwas approvedby theFDAas part of aCNI-free regimen It has been shown toresult in more ACR but better renalfunction and less CAN at 1 and 3 yearscompared with a cyclosporin-based reg-imen18 Long-term outcomes of patientstreated with belatacept are not yet avail-able and it will be interesting to see ifthese early improvements in renal func-tion translate into improvements in graftsurvival

BROADENING THE CONCEPT OFCHRONIC RENAL ALLOGRAFTINJURY

In recent years a broader viewof chronicrenal allograft injury has emerged on thebasis of biopsy data from several largestudies of solitary kidney transplants(arguably a more appropriate studypopulation than bladder-drained simul-taneous pancreas kidney recipients)These studies have used two differentapproaches to investigate the causes ofchronic injurymdashone approach on thebasis of surveillance biopsies in wellfunctioning kidneys and one approachon the basis of biopsies for cause in kid-neys with dysfunction

The conclusions reached by these stud-ies may at first glance seem somewhatdifferent however we believe that theseapproaches are complementary and needto be reconciled if we are to have acomplete picture of chronic graft injuryLongitudinal surveillance biopsy data to

Figure 1 Rates of late renal allograft loss have remained constant (A) KaplanndashMeier cu-mulative graft failure and (B) death-censored graft failure by year of first deceased SCDtransplants from transplant years 1989ndash2008 Reprinted from ref 1 with permission
































































A PATH FORWARD








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A PATH FORWARD








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through a glass darkly: seeking clarity in preventing late kidney

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