How to Maximize Outcomes and Minimize Graft Failure · retransplant, death with a functioning graft) among transplant recipients has ... and BK virus nephropathy. To prevent acute

T H E I M M U N O L O G Y R E P O R T | F a l l 2 0 1 4 21

Kidney transplantation, the best treatment of choice for most patients with end-stage renal disease, is associated with sig-

nificant improvement in quality of life and decreases in mortality risk for most patients when compared with mainte-nance dialysis.1–3

The introduction of induction therapy following kidney transplantation, especial-ly with the use of a lymphocyte-depleting agent in the mid-1970s and calcineurin inhibitor (CNI) therapy using cyclospo-rine in the early 1980s, decreased the rate of acute rejection and improved allograft survival during the first year after trans-plantation. Although 1-year graft survival rates are excellent, long-term graft survival over the past decade has been associated with only modest improvements. The sur-

vival of kidney-transplant recipients is sig-nificantly lower than that of age-matched controls in the general population.4,5 The relatively higher mortality in kidney-transplant recipients partially is due to comorbid medical illness; the duration of dialysis treatment pretransplant; and fac-tors specifically related to the transplant process, including immunosuppression and other drug effects.6,7

Over the past 10 years, the overall rate of graft failure (return to dialysis, retransplant, death with a functioning graft) among transplant recipients has continued to trend downward (6.2/100 patient-years in 2011), although death with a functioning graft has plateaued (Figure 1).8 The main causes of death with a functioning allograft have been cardiovascular disease (31%) and infec-tion (19%; Figure 2).8

In 2013, the United States Renal Data System noted that the percentage of kidney-transplant patients experiencing acute graft rejection had declined steadily over the past decade (Figure 3).8 Despite reduction of acute rejection with improve-ments in overall outcomes following renal transplantation, kidney-allograft loss re-mains common. It is essential to find out

FIGURE 1 Adjusted rate of post-transplant outcomes among first-time adult kidney-transplant recipients. Adapted, with per-mission, from the 2013 USRDS Annual Data Report.8

Rate per 100 patient-yearswith a functioning graft

‘91 ‘93 ‘95 ‘97 ‘99 ‘01Transplant year

‘03 ‘05 ‘07 ‘09 ‘11

10

4

6

8

2

0

All-cause graft failure

Death with function

Return to dialysis or retransplant

Patients (%)

Infection CVD UnknownMalignancy Other

35

25

30

20

10

5

15

0

FIGURE 2 Causes of death with a function-ing kidney graft, 2007–2011. CVD = cardio-vascular disease. Adapted, with permission, from the 2013 USRDS Annual Data Report.8

How to Maximize Outcomes and Minimize Graft FailureThin Thin Maw, MBBSWashington University School of Medicine in St. Louis, St. Louis, Missouri

Abstract Kidney transplantation is the treatment of choice for selected patients with end-stage renal disease. Even though improvements in immunosuppression over the past three decades have significantly improved the early outcomes of kidney transplantation, late allograft failure continues to be an issue for trans-plant recipients and their physicians. The reasons for the lack of improvement in long-term outcomes remain unclear and are likely multifactorial. Chronic al-lograft injury is the consequence of any immunologic or nonimmunologic injury. Nonadherence of transplant recipients is a major cause of chronic allograft injury. Optimizing therapy with an appropriate immunosuppressive regimen, using novel therapeutics, and improving adherence of kidney-transplant recipients are important for extending the life of a renal allograft.

Dr. Maw is Assistant Clinical Professor of Medicine, Renal Division, Washington University School of Medicine in St. Louis, St. Louis, Missouri.

22 T H E I M M U N O L O G Y R E P O R T | V o l u m e 1 1 N u m b e r 1

ThinThinMaw,MBBS How to Maximize Outcomes and Minimize Graft Failure

how to maximize outcomes and minimize renal-allograft failure.

This review is based on an Astellas-sponsored satellite symposium conducted during the 2014 World Transplant Con-gress in San Francisco, California. The panelists included Robert S. Gaston, MD, Professor of Medicine at the University of Alabama at Birmingham; Roy D. Bloom, MD, Medical Director of the Kidney and Pancreas Transplant Program at the Hospital of the University of Pennsylvania in Philadelphia; Arthur J. Matas, MD, Professor of Surgery at the University of Minnesota in Minneapolis; and Flavio Vincenti, MD, Professor of Medicine at the University of California at San Francisco.

n RENAL-ALLOGRAFT SURVIVAL

Despite significant improvements in 1-year kidney-allograft survival, chronic allograft loss after the first year remains common, and the rate has not improved over the past decade. Over the past 20 years, the major improvement in first-year renal-allograft survival has been due to reduced early attrition (Figure 4).9 A number of factors influence short-term graft survival, including delayed graft function, human leukocyte antigen (HLA)

antibodies, type of donor kidney, and do-nor illness, among other factors.

Even though there has been a signifi-cant reduction in early attrition over the years, attrition rates have not improved dramatically, which influences long-term survival. The reasons for the lack of im-provement in long-term survival remain unclear and are probably multifactorial. Possible factors are under immunosup-pression (nonadherence, lack of efficacy), over immunosuppression (infection, ma-lignancy), recurrent disease, poor organ quality, and patient death.

CausesofAllograftLossThe causes of kidney allograft failure

remain unclear. El-Zoghby et al10 inves-tigated the causes of graft loss in 1,317 kidney allografts transplanted between January 1, 1996, and July 1, 2006. A total of 330 grafts (25.1%) were lost, 138 (10.5%) due to death with function, 39 (3.0%) to primary nonfunction, and 153 (11.6%) to graft failure censored for death. In all, more than half (53.6%) of the graft losses were associated with death with func-tion and primary graft nonfunction. The causes of death after kidney transplanta-tion in patients with functioning kidney allografts were related to cardiovascular factors (28.2%), infections (15.2%), ma-lignancies (13.8%), and other (11.6%) or unknown phenomena (31.2%). The causes

of 153 functioning graft losses not due to patient death included glomerular dis-eases (36.6%), fibrosis/atrophy (30.7%), medical/surgical condition (16.3%), acute graft rejection (11.8%), and unclassifiable factors (4.6%).

RiskFactorsforChronicAllograftInjury

The exact mechanisms responsible for chronic allograft injury leading to long-term graft loss are unclear. Both immu-nologic and nonimmunologic dependent factors may contribute to chronic allograft dysfunction. The immunologic factors comprise poor HLA matching, previ-ous sensitization, history of acute graft rejection, inadequate immunosuppres-sion, and patient nonadherence to their medication regimen. Nonimmunologic factors include comorbidities (ie, hyper-tension, diabetes, obesity), older donor or poor organ quality (eg, expanded-criteria donors), acute peritransplant injuries (eg, brain-death injury, ischemia, and/or reperfusion injury), chronic CNI toxicity (eg, nephrotoxicity, hypertension, hyper-glycemia, dyslipidemia), and BK virus nephropathy.

To prevent acute rejection and allograft loss, all kidney-transplant recipients (except between identical twins) require immunosuppressive therapy. Immuno-suppressants are used for induction (ie,

a Attrition of grafts from deceased standard-criteria donors (%)

1989 1994 1999 2004 2009

25

15

20

10

5

0

0–1 year1–3 years3–5 years5–10 years

b Attrition of grafts from living donors (%)

1989 1994 1999 2004 2009

10

6

8

4

2

0

0–1 year1–3 years3–5 years5–10 years

FIGURE 4 Cumulative graft failure, as measured by yearly attrition rate, of first-time kidney transplants from deceased standard-criteria donors (a) and living donors (b). Adapted, with permission, from Lamb et al.9

Acute rejection rate (%)

‘90 ‘92 ‘94 ‘96 ‘98 ‘00Transplant year

‘02 ‘04 ‘06 ‘08 ‘10

60

30

40

50

20

10

0

Deceased donorLiving donor

FIGURE 3 Acute rejection rate first year post transplant among kidney-graft recipients from living and deceased donors, 1990–2010. Dashed line = biopsy-proven acute rejection rate. Adapted, with permission, from the 2013 USRDS Annual Data Report.8



intense immunosuppression during the immediate peri- and post-transplant pe-riod to avert or delay the onset of acute rejection), maintenance immunosuppres-sion, and reversal of established rejection.

n IMMUNOSUPPRESSION IN KIDNEY TRANSPLANTATION

In the 1950s, when clinical renal transplantation began, the first attempts at immunosuppression relied on sublethal total-body irradiation. Administration of azathioprine was introduced in the early 1960s and was soon accompanied by prednisolone. The polyclonal antibody preparations antithymocyte globulin and antilymphocyte globulin became available in the mid-1970s. The introduc-tion of cyclosporine in the early 1980s transformed clinical transplantation into preferred treatment, since it led to significant improvement in graft survival rates. Tacrolimus then was introduced

as an alternative to cyclosporine; use of mycophenolate mofetil (MMF) soon fol-lowed. Daclizumab and basiliximab, hu-manized monoclonal antibodies directed toward the interleukin (IL)-2 receptor (CD25), were approved by the US Food and Drug Administration in 1997 and 1998, respectively, for use after kidney transplantation, based on their capacity to reduce the incidence of acute rejection episodes (Figure 5).8 The mammalian target of rapamycin (mTOR) inhibitor sirolimus became available for clinical immunosuppression in 1999, followed by the mTOR inhibitor everolimus in 2010 and the T-cell costimulation blocker belatacept in 2011.

InductionTherapyA large number of randomized con-

trolled trials and meta-analyses have demonstrated that induction therapy combining a biologic agent with conven-

tional immunosuppressants is superior to conventional therapy alone in reducing kidney allograft rejection and allograft failure.11–13 Therefore, the 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines recommended including a biologic agent as part of the initial immunosuppressive regimen for kidney-transplant recipi-ents.14 The KDIGO guidelines specifi-cally recommended that an IL-2 receptor antagonist, either daclizumab (no longer available) or basiliximab, be used as first-line therapy. However, the guidelines also suggested using a lymphocyte-depleting agent for kidney-transplant recipients who are at high immunologic risk or have risk factors for acute rejection.15

MaintenanceImmunosuppressionMaintenance of immunosuppression

requires the continuous use of immuno-suppressive medications to prevent acute

Patients using calcineurin inhibitors (%)

1995 1999 2003 2007 2011

100

60

80

40

20

0

TacrolimusCyclosporine

Patients using antimetabolites (%)

1995 1999 2003 2007 2011

100

60

80

40

20

0

Mycophenolate mofetilAzathioprine

Patients using mTOR inhibitors (%)

1995 1999 2003 2007 2011

100

60

80

40

20

0

At transplantAt 1 year post transplant

Patients using corticosteroids (%)

1995 1999 2003 2007 2011

100

60

80

40

20

0

At transplantAt 1 year post transplant

Patients using induction agents (%)

1995 1999 2003 2007 2011

100

60

80

40

20

0

IL-2 receptor antagonistsT-cell depleting agentsOtherNone

FIGURE 5 Changes in usage of different classes of immunosuppressive agents by kidney-transplant recipients, 1995–2011. mTOR = mammalian target of rapamycin; IL-2 = interleukin-2. Adapted, with permis-sion, from the 2013 USRDS Data Report.8



graft rejection. Specific medications have changed over the years, but maintenance immunosuppression represents the cornerstone of long-term antirejection therapy. Immunosuppressants currently being used in various combination im-munosuppressant maintenance regimens (dual or triple therapy) include corticoste-roids, azathioprine, MMF, mycophenolate sodium, cyclosporine, tacrolimus, siroli-mus, everolimus, and belatacept. Matas et al15 reported that in the United States, approximately 85% of kidney-transplant recipients were discharged on tacrolimus and MMF, either with (58%) or without (42%) glucocorticoids.

Despite the ability of current im-munosuppressive regimens to reduce the incidence of acute rejection, long-term toxicity related to the use of these drug combinations has become a major challenge. Chronic exposure to CNIs causes arteriolar hyalinosis leading to glomerulosclerosis, tubular atrophy, and interstitial fibrosis. The incidence of CNI nephrotoxicity increases with time after transplant.16 Therefore, there is a great interest in immunosuppressive regimens that permit reduction or elimination of CNIs while maintaining adequate im-munosuppression. Several studies have investigated methods of minimizing, eliminating, or avoiding the use of CNIs.

CNI-SparingRegimensEkberg and others17 explored improve-

ment of long-term renal function and promotion of allograft survival using CNI-sparing regimens. They random-ized 536 patients receiving their first renal transplant into three groups: one was weaned from cyclosporine starting at month 4 post transplant and ending at month 6, a second received low-dose cyclosporine, and the third received standard-dose cyclosporine. The mean glomerular filtration rate (GFR) 12 months after transplantation (primary endpoint) was not statistically different in the cyclosporine-withdrawal and low-dose cyclosporine groups than it was in the standard-dose group. However, the incidence of biopsy-proven acute rejec-tion (BPAR) was significantly higher

in the cyclosporine-withdrawal group (38%) than in the low-dose (25.4%) or standard-dose (27.5%) cyclosporine groups (Figure 6).17

CNI minimization in the SYMPHONY study18 showed that at 3 years after trans-plant, a regimen based on daclizumab induction, 2 g of MMF, low-dose tacro-limus, and a corticosteroid resulted in better renal function (as measured by GFR) and lower acute rejection and graft loss rates than did a regimen using a low dose of cyclosporine or sirolimus instead of tacrolimus and another involving no induction therapy and standard doses of cyclosporine.

Langer et al19 conducted a 12-month randomized, open-label, multicenter trial (ASSET) in de novo renal transplant recipients who received tacrolimus in combination with everolimus, basiliximab induction, and corticosteroids. In the first 3 months of the study, all patients received tacrolimus at daily doses suf-ficient to achieve a target trough level between 4 and 7 ng/mL. Thereafter, about half the patients (n = 109) continued at the same low trough target level, whereas the other half (n = 119) were given lower doses of tacrolimus to maintain a very low trough target level of 1.5–3 ng/mL. Everolimus trough target levels were 3–8 ng/mL throughout the study.

The authors found no statistically significant difference in mean estimated GFR between the low and very low ta-crolimus trough level groups (57.1 vs 51.7 mL/min/1.73 m2), possibly due to overlap-ping tacrolimus exposure levels.19 The in-cidence of BPAR during months 4–12 and the frequency of serious adverse events over the full course of the study also were comparable between the two groups.19 Thus, an everolimus-facilitated tacrolimus minimization regimen achieved good renal function, low BPAR and graft-loss rates, and an acceptable safety profile in renal-transplant recipients over 1 year, although statistically superior renal func-tion was not achieved in the 1.5–3 ng/mL tacrolimus trough level group.

A number of randomized controlled trials have focused on CNI elimina-tion with mTOR inhibitors using either sirolimus or everolimus. Schena and colleagues20 conducted CONVERT, a prospective, randomized, multicenter clinical trial that assessed the safety and efficacy of converting renal-allograft re-cipients from CNI maintenance therapy to sirolimus-based immunosuppression. In all, 830 renal-transplant recipients who were 6–120 months post transplant and receiving cyclosporine or tacrolimus were randomly assigned to continue their CNI regimen or converted to sirolimus.

At 2 years, sirolimus conversion among patients with a baseline GFR > 40 mL/min was associated with excellent patient and graft survival, no difference in BPAR, increased urinary protein excretion, and a lower incidence of malignancy when compared with CNI continuation. How-ever, the enrollment of patients having a baseline GFR = 20–40 mL/min was halted prematurely because of a higher incidence of safety endpoints (eg, biopsy-confirmed acute rejection, graft loss, or death at 12 months) in the sirolimus conversion arm.

It should be noted that the use of mTOR inhibitors plus a CNI minimi-zation regimen has nonrenal benefits, including a reduced incidence of cyto-megalovirus infection, lower risk of BK viremia, and reduced intimal proliferation in heart-transplant recipients.

Vincenti and others21 conducted a ran-

Patients with BPAR (%)

6 Months 12 Months

50

30

40

20

10

0

CsA withdrawalLow-dose CsAStandard-dose CsA

P = 0.027

P = 0.04

FIGURE 6 Proportion of kidney-transplant patients with first biopsy-proven acute rejection (BPAR) at 6 and 12 months. CsA = cyclosporine. Adapted, with permission, from Ekberg et al.17



domized, active-controlled, multicenter, phase 3 study comparing administration of a more-intensive (MI) or less-intensive (LI) belatacept regimen with the use of cyclosporine in adult kidney-transplant recipients. At month 12, both belatacept regimens produced similar patient or graft survival when compared with cy-closporine. However, patients receiving belatacept had superior renal function, as measured by a composite renal im-pairment endpoint (MI, 55%; LI, 54%; cyclosporine: 78%; P ≤ 0.001 for either belatacept regimen vs cyclosporine) and GFR (65, 63, and 50 mL/min, respectively; P ≤ 0.001 for either belatacept regimen vs cyclosporine). But this superiority of belatacept came with a price: a higher rate of early acute rejection and a higher frequency of post-transplant lymphopro-liferative disorder.

SummaryCurrent CNI-based immunosupres-

sive regimens may not be optimal for improving long-term outcomes, since nephrotoxicity and metabolic abnormali-ties (new-onset diabetes after transplant, hyperlipidemia, and hypertension) are unavoidable and contribute to premature death and graft loss. Even though the use of CNI-minimization regimens reduces toxicities, it may not benefit patients over the long term and may contribute to an increase in chronic antibody-mediated rejection as a cause of late graft failure.

n MEDICATION ADHERENCE

Nonadherence is an important risk factor for renal graft loss over the long term.22–25 An accurate assessment of the frequency of medication nonadherence and its contribution to allograft loss is difficult because of the wide variability in study designs and results.

Post-transplant nonadherence is com-mon and has been reported in 5%–45% of renal-transplant patients.25 Schweizer et al26 conducted a retrospective and prospective study of medication noncom-pliance and follow-up care in 538 kidney-transplant recipients. The retrospective chart review of 260 patients transplanted between 1971 and 1984 revealed a medi-

cation nonadherence incidence of 18%, of which 91% of patients either lost their grafts or died. The prospective study also revealed a 15% nonadherence rate. Nonadherent behavior was usually not predictable and often had no identifiable reason.

Nonadherence rates increase dramati-cally > 6 months post transplantation. However, nonadherence is likely un-derestimated, because many studies are based on patient self-reporting. Gaston and colleagues27 evaluated the role of nonadherence in graft loss. The grafts of 1,005 kidney-transplant recipients sur-vived for > 6 months between 1992 and 1995. However, 184 patients subsequently lost their grafts over 48 ± 11 months. The graft loss initially was attributed to

chronic rejection. In all, 83 patients had chronic rejection, and 48 (26% of patients who lost their grafts) had not adhered to their maintenance immunosuppressive regimen. Medication nonadherence was deemed to be the primary cause of graft loss at their center.

RateofNonadherenceAfterTransplant

The prevalence of nonadherence varies widely and depends upon the definitions of nonadherence used, case finding, and measurement methods.

Butler et al25 performed a meta-analysis of 36 cross-sectional, cohort studies, and case series. The odds of graft failure were seven times greater among nonadherent

kidney-transplant recipients than among their adherent counterparts (odds ratio = 7.1; 95% confidence interval, 4.4–11.7; P < 0.001). Development of standardized methods to assess medication adherence in clinical populations and institution of effective interventions to increase adherence may improve graft survival significantly.

Denhaerynck and others28 performed a literature review on the prevalence, conse-quences, and determinants of medication nonadherence in adult renal-transplant recipients. The mean prevalence of self-reported nonadherence was 28%. Nonad-herence was associated with poor clinical outcomes, contributing to 20% of late acute-rejection episodes and 16% of graft losses. Further, consistent determinants of nonadherence were younger age, social isolation, and cognitive perceptions (eg, low self-efficacy, certain health beliefs).

ImpactofMedicationNonadherenceAs observed at the beginning of this

review, while 1-year allograft survival has improved significantly, long-term survival of kidney transplants has improved little over the previous decade. Late kidney-graft loss has been attributed to death with a functioning graft and chronic graft rejection, a phenomenon associated with chronic allograft nephropathy, interstitial fibrosis, and tubular atrophy. Medication nonadherence has been linked to graft dysfunction, chronic graft rejection, graft loss, and the presence of donor-specific antibodies (DSAs). Nonadherence has a significant impact on graft survival.

Sellarés et al29 prospectively studied bi-opsies of kidney-transplant patients who progressed to graft failure after a biopsy was performed to identify a cause. Fail-ure was rare after T-cell–mediated graft rejection and acute kidney injury and was common after antibody-mediated rejec-tion. Among patients who experienced loss of a kidney graft due to rejection, 17 of 36 (47%) were independently identified as being nonadherent by their physicians (Figure 7).29 In addition, nonadherence was more frequent among patients whose grafts progressed to failure than among those with viable grafts (32% vs 3%).

While 1-year allograft survival has improved significantly, long-term survival of kidney transplants has improved little over the previous decade.



Thus, a common cause of graft loss is antibody-mediated rejection, which has been correlated with nonadherence in up to one half of cases.

Graft survival is associated with de novo donor-specific HLA antibody (dnD-SA) formation. Nonadherent patients are more likely to have developed dnDSAs. In a prospective study, Wiebe et al30 fol-lowed 315 consecutive kidney transplants without pretransplant DSAs for a mean of 6.2 ± 2.9 years. In all, 47 of 315 patients (15%) developed dnDSAs. Independent predictors of dnDSA were HLA-DR1 mismatch and medication nonadherence. A total of 23 of 47 patients (49%) who developed dnDSAs were nonadherent with their immunosuppressive regimen. Median 10-year graft survival was lower for those with dnDSAs than for the group without dnDSAs (57% vs 96%; P < 0.001).

IdentifyingNonadherentPatientsMedication nonadherence is difficult

to detect until it presents as graft rejection. Adherence can be determined by objective measures (eg, direct observation, serum or plasma drug levels, pill counts, refill records, and electronic monitoring) and by subjective measures (self-reporting). There is no perfect measure of adher-ence in clinical practice. More than one approach should be used to identify and measure nonadherence.

Dew et al31 performed a meta-analysis

of 147 studies of kidney, heart, liver, pancreas, kidney-pancreas, lung, and heart-lung recipients that were published between 1981 and 2005. A limited num-ber of studies investigated individual psy-chosocial risk factors with nonadherence outcomes. Few significant psychosocial variables (nonwhite ethnicity, poorer social support, and poorer perceived health) were significantly associated with greater immunosuppressant nonadher-ence. Other risk factors for nonadherence that were reported in subsequent studies included inability to make co-payments, patients’ beliefs about immunosuppres-sive medications, perceived lower life satisfaction and graft longevity, younger age, male gender, and receipt of a graft from a living donor.

ApproachesforManagingNonadherence

There is no single cause for nonadher-ence, so it is difficult to have one effective intervention for its management. Success-ful intervention to improve medication adherence requires a team approach. Combinations of strategies that focus on patient education programs, convenience of the dosing regimen, social media, and electronic systems may be effective in the long term.

De Bleser and others32 systematically reviewed 12 trials designed to minimize post-transplant medication nonadherence

and identified a number of weaknesses in the studies. Only five studies were ran-domized, controlled trials that found a statistically significant improvement in at least one medication-adherence outcome with the intervention. Therefore, no single intervention was better at increasing medication adherence than any other, but a combination of interventions provided by a team may be the best approach to improve long-term outcomes.

Another way to improve medication adherence is to simplify the dosing regi-men. Several studies have shown once-daily dosing to be significantly associated with improved adherence compared with twice-daily or more frequent dosing. However, complex immunosuppressive regimens make interpretation of these results difficult, especially since immu-nosuppressants are generally taken once or twice daily.

Kuypers and colleagues33 performed a randomized, multicenter, controlled trial to evaluate differences in medica-tion adherence between patients taking tacrolimus once daily and those taking the drug twice daily. An electronic monitor documented drug intake. A total of 219 patients were analyzed; 145 were dosed once daily, and 74 were dosed twice daily. At 6 months after randomization, 81.5% of the once-daily group and 71.9% of the twice-daily group had continued taking the drug (P = 0.082). A total of 88.2% of the once-daily group and 78.8% of the twice-daily group took the prescribed number of daily doses, a significant dif-ference (P = 0.009). Implementation of once-daily dosing of tacrolimus was therefore associated with significantly higher adherence than twice-daily dosing.

Given the potentially devastating consequences of nonadherence to immu-nosuppressant therapy, clinicians should pay attention to medication adherence and discuss and monitor adherence with transplant recipients to improve long-term outcomes.

n LONG-TERM GRAFT SURVIVAL AND OUTCOMES

Long-term renal allograft survival in the United States has made small but mea-

Probable ABMR (9%)

Mixed rejection (5%)

Glomerulo-nephritis (18%)

Medical/surgicalconditions (11%)

Polyomavirusnephropathy (7%)

Adherent (53%)

Nonadherent (47%)

ABMR (50%)

64% ABMR, probable ABMR, or mixed rejection

FIGURE 7 Role of antibody-mediated rejection (ABMR) and medication nonadherence among 60 kidney-transplant recipients who progressed to graft failure. Almost one half of these episodes (47%) were due to nonadherence. Adapted, with permission, from Sellarés et al.29



Graft survival

Months post transplant24 36 48 6012

1.0

0.8

0.9

0.7

0.6

0.5

0.4

0.3

NormalFibrosis onlyFibrosis and in�ammationTransplant glomerulopathy

FIGURE 8 Relationship between histologic classification at biopsy and primary end-point of graft/glomerular filtration rate loss (P < 0.001; log-rank analysis). Adapted, with permission, from Cosio et al.34

Graft survival (%)

Months from entry biopsy6 12 18 240

100

90

80

70

60

50

40

C4d–/DSA–C4d–/DSA+C4d+/DSA–C4d+/DSA+

FIGURE 9 Kaplan-Meier analysis of the impact of antibody-mediated injury, as evi-denced by the presence (+) or absence (–) of C4d staining and circulating donor-specific antibody (DSA) positivity, on kidney allograft survival among 173 patients with new-onset late kidney graft dysfunction. Adapted, with permission, from Gaston et al.35

surable progress over the years. Identify-ing factors that may predict allograft loss is an important step toward prolonging kidney allograft survival.

Cosio et al34 explored the association between histologic changes on 1-year surveillance biopsies and changes in graft function and survival. This study included 292 adult renal-allograft recipients; be-tween 1998 and 2001, organs were trans-planted from living or deceased donors, and patients were followed for an average of 46 ± 14 months. Fibrosis, inflamma-tion, and transplant glomerulopathy were related to poorer survival, whereas mild fibrosis alone was not. Inflammation and glomerulopathy 1 year post transplant predicted loss of graft function and graft failure independent of function and other variables (Figure 8).34

Gaston and others35 conducted an observational multicenter trial known as the Long-Term Deterioration of Kidney Allograft Function (DeKAF) study to identify modifiable variables that cause late allograft failure. They included 173 patients transplanted before October 1, 2005 (mean time after transplant, 7.3 ± 6.0 years), who had a baseline serum creati-nine level of 1.4 ± 0.3 mg/dL before Janu-ary 1, 2006. Patients underwent biopsy for new-onset graft dysfunction after that

date (mean creatinine level at biopsy, 2.7 ± 1.6 mg/dL). The patients were analyzed by subgroup based on C4d staining and DSA status: group A was C4d–, DSA– (n = 71); group B was C4d–, DSA+ (n = 34); group C was C4d+, DSA– (n = 28); and group D was C4d+, DSA+ (n = 40). Among DSA+ recipients (groups B and D), those in group D had broader reactivity and a stronger DSA response than the C4d– patients in group B. After 2 years, groups C and D (C4d+) were at significantly greater risk for late graft failure and worse outcome than the C4d – patients in groups A and B (Figure 9).35 The immunologic insult (antibody-mediated injury) was substan-tially important in influencing long-term outcome when compared with the relative significance of nonimmunologic factors and progressive CNI toxicity.

Woodle and colleagues36 performed a 5-year prospective, randomized, double-blind, placebo-controlled, multicenter trial that compared early (7 days) cor-ticosteroid cessation versus long-term, low-dose corticosteroid therapy. No differences in renal allograft survival and function at 5 years were observed between the two groups. Although early corticoste-

roid withdrawal was associated with less weight gain and improvement in serum triglyceride levels, it also increased the rate of BPAR (corticosteroid-sensitive).

n CONCLUSION

Major advances achieved over the past decade have reduced the risk of acute graft rejection and increased short-term renal allograft survival. However, improving the long-term attrition rate in patient and graft survival remains challenging. Developing better immunosuppression strategies, introducing novel and less toxic agents or regimens, decreasing medication nonadherence, and address-ing cardiovascular comorbidities such as hypertension and dyslipidemia should help to minimize graft failure and improve long-term outcomes.

A new paradigm in immunosuppres-sion is required to improve long-term outcomes. New biologic agents should be designed to suppress both T and B cells, have less nephrotoxicity than current agents, not aggravate cardiovascular risk factors, not affect glucose metabolism, and improve adherence by requiring no more than once-daily dosing.

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How to Maximize Outcomes and Minimize Graft Failure · retransplant, death with a functioning graft) among transplant recipients has ... and BK virus nephropathy. To prevent acute