C 2011 The Authors

C 2011 The American Society of
Journal compilation 
Transplantation and the American Society of Transplant Surgeons

American Journal of Transplantation 2011; 11: 15701575

Wiley Periodicals Inc.

Minireview

doi: 10.1111/j.1600-6143.2011.03677.x

Surveillance Protocol Kidney Transplant Biopsies:

Their Evolving Role in Clinical Practice
Introduction

L. K. Henderson, B. J. Nankivell
and J. R. Chapman*
Department of Renal Medicine, Westmead Hospital,
University of Sydney, Sydney, Australia
Corresponding author: Jeremy R. Chapman,
Jeremy_Chapman@wsahs.nsw.gov.au
Protocol renal allograft biopsies at fixed time points
from transplantation have aided research and provided
insights into the pathogenesis of early and late allograft injury. Their role is evolving from research to a
clinical management tool needed to detect subclinical
pathology requiring treatment adjustment. They frequently reveal unexpected findings and influence therapy in the majority of patients. Detection of subclinical
rejection (SCR) remains important despite declining
prevalence with triple therapy, the evidence favors
treatment, if found. Surveillance biopsies in steroid
avoidance and calcineurin inhibitor (CNI) withdrawal
programs provide an important safety net against the
increased rates of late acute and SCR. Individualization of therapy in high-risk patients and safe reduction
of immunosuppression in standard risk individuals becomes possible. Other potentially reversible chronic
pathologies that may be detected, include chronic Tcell or antibody-mediated rejection, recurrent disease,
BK virus-associated nephropathy, interstitial fibrosis
and tubular atrophy and CNI nephrotoxicity, allowing
modifications of therapy to limit ongoing graft injury.
Biopsy is safe and inexpensive compared with costs of
earlier graft failure and return to dialysis. This review
summarizes current evidence on use of surveillance
histology for the clinical practice of renal transplantation.
Key words: Calcineurin nephrotoxicity,
biopsy, subclinical rejection, surveillance

protocol

Abbreviations: AR, acute rejection; BKVAN, BK virusassociated nephropathy; BL, borderline changes; CAN,
chronic allograft nephropathy; CNI, calcineurin inhibitor; DSA, donor-specific antibodies; GN, glomerulonephritis; HLA, human leukocyte antigen; IF/TA, interstitial fibrosis and tubular atrophy; IL2RA, IL-2 receptor antagonist; MMF, mycophenolate mofetil; PVAN,
polyoma virus-associated nephropathy; SCR, subclinical rejection; TG, transplant glomerulopathy; +XM,
positive crossmatch.
Received 3 February 2011, revised 18 May 2011 and
accepted for publication 26 May 2011
1570

Protocol, management or surveillance renal allograft biopsies have provided insight into pathogenesis and guided
clinical management since the 1980s (1). Routine assessment of pathology at fixed time points irrespective of renal
function, has led to major advances in our understanding
of the pathophysiology of graft injury and the sequence of
events leading to late allograft failure.
Early detection and treatment of subclinical rejection
(SCR), before renal dysfunction, improves outcomes
(24). Decreased prevalence of SCR with potent immunosuppression reduces this benefit in standard risk recipients, but utility is retained when transplanting high-risk
patients and for monitoring steroid or calcineurin inhibitor
(CNI) withdrawal (5). Biopsy is undertaken in multiple different environments ranging from dedicated outpatient facilities allowing 4-hour discharge, through to expensive
multidisciplinary in-patient admissions. The justification for
protocol biopsy has been misunderstood by some as an
experimental procedure, rather than as part of a standardized program of clinical surveillance to detect subclinical
pathology.
The aim of this review is to summarize current evidence on
the use of surveillance histology in clinical management of
renal transplant recipients.
Subclinical rejection
Burdick et al. found lymphocytic infiltrates in protocol biopsies at 1 and 4 weeks after transplantation from patients
with normal graft function (1). Termed SCR by Rush using
the Banff schema, it occurred in 30% of well-functioning
grafts by 3 months after transplantation using cyclosporinebased immunosuppression (6,7). Nankivell noted SCR in
45.7% at 3 months was associated with greater interstitial fibrosis and tubular atrophy (IF/TA) by 12 months (8).
Legendre confirmed the association of clinically silent persistent inflammation with chronic tubulointerstitial damage
(9) and others have reported impact on survival of fibrosis
and inflammation compared with fibrosis alone (1012).
Rush et al. randomized 72 low-risk deceased donor renal transplant recipients treated with cyclosporine, azathioprine and prednisolone, to biopsy at 1, 2, 3, 6 and 12
months with steroid treatment when SCR was detected,
or to a control group biopsied at 6 and 12 months and

The Clinical Role of Protocol Biopsy

treated only for clinical episodes of rejection. Treated SCR

was associated with less clinical rejection, reduced chronic
tubulointerstitial scores at 6 months and lower serum creatinine at 24 months, but treatment of SCR identified at
6 months did not prevent deterioration of renal function
between 6 and 24 months (7).
In a second multicenter study, Rush et al. randomized
121 patients receiving tacrolimus, mycophenolate mofetil
(MMF) and prednisolone to biopsy at 0, 1, 2, 3 and 6
months, versus 0 and 6 months with treatment of SCR in
both arms. Overall prevalence of SCR had fallen to 4.6% in
the biopsy arm, which was attributed to the more potent
immunosuppression, thus there was no benefit to early
protocol biopsies with tacrolimus and MMF therapy (13).
In the third study of SCR, Kurtkoti et al. randomized 102
recipients of living-donor transplants to protocol biopsy at
1 and 3 months or to indication biopsy alone. Immunosuppression comprised a CNI (cyclosporine or tacrolimus),
antimetabolite (azathioprine or MMF) and prednisolone.
Histologically proven acute rejection (AR), acute SCR and
borderline changes (BL), were treated with steroids. Renal
function was significantly better at 6 months and 1 year
in the biopsy arm, and they concluded that protocol biopsies allowed detection and treatment of early SCR with
improved short-term allograft function (2).
Observational studies have shown that persistent inflammation, even below the Banff threshold diagnosis for acute
rejection, results in worse graft function at 1 and 2 years
(14). Furthermore, surveillance biopsies carried out as early
as 14 days after transplantation showing SCR predict a
30% decrease in graft survival rates at 10 years from
transplant (3). Data from nonrandomized studies in both
adults and pediatric patients treated with cyclosporine or
tacrolimus, MMF and steroids suggest that treatment of
SCR with steroids reduces chronic inflammation (4,15).
The appropriateness of treating BL with steroids has been
questioned with recent evidence that regulatory T cells
are present in renal allografts with BL, demonstrated by
increased Foxp3 gene expression in peripheral blood (16).
Further studies will be required to identify any predictive
role for Tregs and the level of Foxp3 expression in protocol
biopsies.
The relationship between different immunosuppression
protocols and incidence of subclinical changes has been reported in a four-way cohort study, demonstrating reduced
SCR with CNI combined with sirolimus compared to MMF
(17). Two recent studies comparing cyclosporine and azathioprine with tacrolimus, MMF and IL2RA, described reduced SCR with tacrolimus, and no significant differences
in graft survival, renal function and subsequent rejection if
borderline changes (18) or SCR (19) were untreated. Only
2 of 18 patients were treated in the first study, follow-up
was short at 1 year and Banff chronicity scores were not
reported (18). The second study reported rates of IF/TA
American Journal of Transplantation 2011; 11: 15701575

between 53% and 63% in both groups as well as an association of SCR with a CAN score 2 in the same 6-month
biopsy (19). Of greater concern is a 27% prevalence of
SCR in one and 4-month protocol biopsies found in patients undergoing rapid steroid withdrawal, comparable to
rates seen in the cyclosporine/azathioprine era. SCR was
followed by greater IF/TA scores at 1 year with an odds ratio
of 6.62 (95% CI 2.6816.3; Ref. 5). The prospect of uncontrolled subclinical alloimmune injury in patients undergoing
increasingly popular regimes of steroid withdrawal is supported by studies of troubled transplants where rejection appears again as a major cause of failure. A major role
for surveillance pathology may be to protect steroid-free
patients from the effects of SCR.
The evidence favors treating SCR when diagnosed early after transplantation. While the incidence of SCR has fallen
with current potent immunosuppression, it cannot be assumed the rates of SCR will be low with reduced levels
of immunosuppression. Recent studies are hampered by
small numbers and short follow-up periods, which are unable to measure the long-term impact of undetected or
untreated SCR on chronic fibrosis and outcomes.

Subclinical rejection in sensitized recipients

Many transplant centers now use desensitization protocols to overcome immunological barriers such as anti-HLA
donor specific antibodies (DSA) or blood group incompatibility (ABOi) that previously precluded transplantation.
Gloor et al. examined the incidence of SCR in 14 positive
cross-match living donor transplants who were desensitized before transplantation. Surveillance biopsies on days
3, 7, 14, 28 and 90 revealed a mean prevalence of subclinical antibody-mediated rejection of 29%, requiring treatment with plasma exchange and corticosteroids resulting
in resolution of histology on 3- and 12-month biopsies and
stabilization of renal function in all patients (20).
In a retrospective case series of 116 surveillance biopsies
from 50 stable positive crossmatch (+XM) desensitized
patients, Kraus et al. treated subclinical cellular rejection in
40% of biopsies between 0 and 2 months, falling to 17%
by 9 months. No differences were found in 1-year serum
creatinine with or without SCR, postulated to be due to
early intervention. Elimination of circulating DSA correlated
with absence of on-going antibody mediated injury in the
graft and a low risk of SCR but C4d positivity was not a
helpful predictor of rejection or severity of rejection (21).
Setoguchi et al. found that the incidence of subclinical cellular rejection increased with time in ABO incompatible
(ABOi) recipients. BL and SCR were treated with steroids
with the majority of grafts in both groups showing normal
histology or mild IF/TA and no difference in GFR or graft
survival. However, interstitial inflammation with IF/TA was
significantly higher in ABOi transplants at 612 months and
was associated with a worse outcome (22).
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Henderson et al.

The development of preformed (21) or de novo (23,24)

anti-HLA DSA has been shown to correlate with acute humoral rejection and is a significant risk factor for transplant
glomerulopathy (TG) and graft loss. Posttransplant monitoring of DSA is neither a sensitive nor specific test for
predicting graft pathology and thus is not a substitute for
histopathology.
Surveillance biopsy in high immunological risk patients allows early detection of acute or subclinical AMR: providing either preemptive treatment with potential better outcomes or reassurance of adequate immunosuppression
with normal histology. Recent studies have revealed a very
different histological and clinical course when compared
with standard risk transplants and allowed correlation with
persistent DSA, C4d deposition and prior humoral rejection
with graft histology and function (21,22).
Implantation biopsy
Implantation biopsy is standard of practice as a baseline for
assessing subsequent changes. Glomerulosclerosis, vascular changes, tubular atrophy and interstitial fibrosis have
all been associated independently with graft outcome. Incorporating histopathology into a clinical scoring system
(25) or composite score (26) has improved predictive value
of pretransplant biopsies.
Delayed graft function
Grafts with delayed graft function (DGF) are at higher risk of
acute rejection, and associated with inferior graft outcome.
Acute rejection cannot easily be diagnosed in the setting of
DGF without surveillance biopsy and is standard of practice
globally. In addition to acute tubular necrosis, subclinical AR
has been reported in 1821% and BL in 1236% of such
surveillance biopsies (27,28).
Interstitial fibrosis/tubular atrophy (IF/TA)
Surveillance biopsies have allowed greater understanding of the cumulative impact of donor disease, ischemiareperfusion injury at the time of organ procurement, acute
and SCR and CNI toxicity, in the early months after transplantation. Abnormalities are present in up to 40% of implantation biopsies, dependent on donor age and quality
and on organ recovery (29). Surveillance biopsies have
identified donor age, DGF, severe vascular AR and SCR
as independent variables as risk factors for IF/TA (8,30).
Severe IF/TA has been reported in 58% of patients by
10 years and once established, was irreversible and accompanied by deterioration in graft function (8).
Graft function is an unreliable marker of the underlying
severity of graft pathology. Legendre et al. reported the
prevalence of IF/TA as 25% at 3 months and 50% at 2 years
et al.
in 41 patients with normal graft function (9) and Seron
described progression of chronic lesions (Banff ci, ct, cg
and cv scores) between 4 and 14 months without changes
in graft function (31). In contrast to SCR, IF/TA increases
with time and when superimposed on chronic transplant
1572

arteriopathy, SCR or glomerulopathy, there is significantly

worse survival, with inflammation combined with fibrosis
providing the worst outcome (3,10,14).
Surveillance biopsies detect early changes while graft function is still normal, allowing early intervention designed
to decelerate or abrogate development of chronic fibrosis
and ultimately improve graft survival. Oberbauer et al. described less IF/TA at 3 years and improved graft survival at
4 years after withdrawal of CNI at 3 months in low immunological risk patients receiving cyclosporine A and sirolimus
correlating progression of IF/TA with graft survival (32).
CNI toxicity
Surveillance biopsies have shown that CNIs reduce the
incidence of early SCR and modulate IF/TA (33) but the
penalty from chronic CNI-nephrotoxicity needs to be understood. Nankivell et al. described pathological changes
of cyclosporine nephrotoxicity, associated with microvascular and glomerular changes. An early reversible pattern
of nephrotoxicity associated with acute functional nephrotoxicity and high cyclosporine levels was followed by a
later chronic, persistent pattern with a median onset at
3 years, which was usually irreversible. Both cyclosporine
and tacrolimus produced similar fibrogenic effects in the
kidney and a similar pattern of nephrotoxicity (34).
Flechner et al. found that sirolimus combined with MMF
and steroids produced better renal function and less IF/TA
compared with cyclosporine-based therapy at 2 years (35).
Similar improvements in IF/TA with non-CNI based regimens have also been shown by Vincenti et al., who
randomized 218 renal transplant recipients to belatacept
versus cyclosporineacute rejection rates were similar
but a higher GFR and less tubulointerstitial damage occurred in the belatacept groups with maximum benefit
in low risk patients receiving standard criteria kidneys
compared with those receiving extended criteria donor
kidneys (36,37).
Recent data question the specificity of lesions related to
CNI therapy. Naesens et al. found neither tacrolimus dose
nor measures of systemic exposure were associated with
lesions of CNI nephrotoxicity (38). Stegall et al. have subsequently described a similar prevalence of arterial hyalinosis
at 5 years in tacrolimus versus a mixed group of sirolimustreated kidney transplant recipients, though the sirolimus
group was small and preimplantation histology was not
reported (39).
While CNIs maintain their overall superiority as first-line
immunosuppressive agents, surveillance biopsy usefully
identifies CNI nephrotoxicity.
Viral nephropathies
Polyoma virus associated nephropathy (PVAN or BKVAN)
has a reported incidence of 35%. Although prevalence
is low, BKVAN results in up to 45% graft loss in affected
American Journal of Transplantation 2011; 11: 15701575

The Clinical Role of Protocol Biopsy

individuals (40) and early diagnosis is necessary to resolve

infection and prevent chronic damage.
The most specific surrogate markers of renal parenchymal
involvement with BK are persistent viuria (107 copies/mL)
and increasing viremia (104 copies/mL for >3 weeks) independent of renal function (41). Early modification of immunosuppression may favor stable graft function and viral
clearance thus a surveillance biopsy can help to quantify
the immune risk, with reduction in immunosuppression
safe with a normal biopsy. Buehrig et al. found all patients
with BKVAN diagnosed by surveillance biopsies (at 34
and 12 months) and managed by immunosuppression reduction had a satisfactory outcome by 6 months after diagnosis, compared with late diagnosis by indication biopsies where 70% had graft loss, functional or histological
deterioration (42).
Chronic antibody mediated rejection and TG
TG is an important cause of late graft failure. Surveillance
biopsies have shown that glomerulopathy can be detected
as early as 1 month after transplantation (43) and severely
compromise graft survival (10).
Gloor et al. reported a cumulative incidence of clinical and
subclinical TG increasing from 4% at 1 year to 20% by
5 years, with prior acute rejection, hepatitis C and sensitization to anti-HLA antibodies (especially Class II) being risk
factors (44). This group also reported a significantly higher
incidence of TG in ABOi and +XM patients compared with
conventional transplants. Humoral rejection was the greatest predictor of abnormal 1-year histology but not of graft
survival (45). Longer follow-up studies are required to determine the ultimate impact of early humoral rejection. So
while preliminary data confirm early detection of chronic
antibody mediated rejection is feasible, the current problem is the lack of proven treatment options for established
TG.
Recurrent and de novo glomerulonephritis
Clinical diagnosis prompted by hematuria and/or proteinuria leads to reported recurrence rates ranging from 10 to
20%. This is likely to be an underestimate as much disease is subclinical (46) and immunofluorescence and electron microscopy are often not routinely performed. Surveillance biopsies confirm a higher prevalence of certain GN
than previously reported (47,48) with unsuspected recurrent GN in approximately 12% of surveillance biopsies.
Recurrence rates between 42% and 55% have been reported in certain GN such as membranous nephropathy
and lupus nephritis (47,48).

ients. Two large retrospective audits support the argument that surveillance biopsy can be safely performed
with major complications occurring in 0.41.0% of patients
(49,50). In many units, protocol biopsies have transitioned
from research investigation to clinical monitoring, specifically incorporated in steroid avoidance and CNI-withdrawal
programs.
A recent unpublished audit of the role of 280 surveillance
biopsies in 100 sequential predominantly low-risk recipients in our own unit found widespread unsuspected subclinical pathological abnormalities in 50% of samples, including acute and borderline SCR, IF/TA, CNI toxicity as
well as recurrent disease and BKVAN. Management was
consequently changed in 56% of our patients.
Optimum timing of surveillance biopsies depends on the
pathology sought. Biopsies up to 3 months from transplant
show a higher frequency of SCR with a greater incidence
of IF/TA beyond 6 months and presentation of recurrent
and de novo GN, TG and CNI toxicity occurring at various
time points from transplantation. Early surveillance biopsy
yields the greatest reversible pathology while biopsies beyond 1 year serve as prognostic indicators of graft survival and help tailor immunosuppression according to the
individual.
Sampling error of up to 25% has been reported in surveillance biopsies (51) and may limit interpretation. Changes in
the Banff schema has improved interobserver agreement
but if histology is to be used reliably as a surrogate marker,
assessment needs to be quantitated. Morphometry and
image analysis have been used as an efficacy variable but
have yet to be validated and interobserver variability remains an issue depending on the renal lesion assessed
(52).
While renal biopsy remains the current gold standard
for investigation and assessment of allograft pathology, development of either supplementary molecular methods or
minimally monitoring or noninvasive monitoring have been
expanded in recent years.
Several groups have compared urinary biomarkers with histology from surveillance biopsies for the detection of subclinical pathology in renal allografts (53). Analysis of gene
expression from surveillance and indication biopsies has
helped understanding of the role of molecular analysis in
detecting rejection and tolerance. However, reliable analysis and interpretation of the ensuing molecular data currently still needs correlation and validation with histology
from indication and surveillance biopsies, as well as other
robust markers of graft outcome and survival.

Future Directions
In the last 20 years, surveillance biopsies have provided
insight into the pathogenesis of chronic injury, and guided
clinical decision-making in both low- and high-risk recipAmerican Journal of Transplantation 2011; 11: 15701575

It is our view that whenever immunological barriers are

challenged in renal transplantation, the need for surveillance pathology remains strong. This applies to protocol reduction of immunosuppression from CNI or steroid
1573

Henderson et al.

withdrawal or avoidance, and especially to trials of tolerance protocols and novel immunosuppressive agents.
Transplantation of high-risk, cross-match positive, highly
sensitized or ABO-incompatible recipients and use of extended criteria donors and donors after cardiac death also
require careful, effective and accurate monitoring using
surveillance histology.

Conclusions
Optimal long-term clinical management of kidney transplants with preservation of function is paramount both for
the individual and community. Judicious use of the information gathered from surveillance pathology with appropriate changes in therapy offers the potential of better longterm outcomes. The cost, risk and patient inconvenience
of surveillance biopsies must be weighed against potential
gains from early interventions guided by the findings.

Disclosure
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of
Transplantation.

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