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Volume: 12 Issue: 4 August 2014

FULL TEXT

ARTICLE
Pathologic Characteristics of Early or Late Acute Cellular Rejection and Outcome After Kidney Transplant

Objectives: To determine the pathologic features of early- and late-onset acute cellular rejection that may contribute to graft loss after kidney transplant.

Materials and Methods: There were 247 patients who had acute cellular rejection included in the study. The biopsy that showed the highest acute cellular rejection severity was evaluated for each patient (total, 247 biopsies) and classified as early (time of biopsy, ≤ 6 mo) or late (time of biopsy, > 6 mo) acute cellular rejection.

Results: The mean scores of interstitial inflammation (interstitial inflammation and tubulitis), scarring (interstitial fibrosis/tubular atrophy), and vascular disorders (arteriolar hyaline thickening and vascular intimal fibrosis) were significantly higher in late than early acute cellular rejection. Death-censored graft survival at 8 years after kidney transplant was higher in patients who had early (88%) than late acute cellular rejection (66%; P ≤ .001). Early and late acute cellular rejection with either low- or high-grade interstitial fibrosis/tubular atrophy had similar death-censored graft survival. In patients who had late acute cellular rejection, death-censored graft survival was significantly higher when there was low- (survival, 79%) than high-grade vascular intimal fibrosis (survival, 48%; P ≤ .006). Long-term graft loss was significantly associated with the number of biopsies, intimal arteritis, and tubulitis in patients who had early acute cellular rejection, and vascular intimal fibrosis in patients who had late acute cellular rejection.

Conclusions: High-grade vascular intimal fibrosis was a risk factor for poor long-term graft survival in late acute cellular rejection after kidney transplant.


Key words : Graft biopsy, End-stage renal disease, Interstitial fibrosis and tubular atrophy, Graft survival, Interstitial inflammation, Vascular disorders

Introduction

Renal allograft rejection is a major risk factor contributing to long-term graft loss, and may occur at several minutes (hyperacute), days to weeks (acute), 3 months (late acute), or months to years (chronic) after transplant.1,2 Rejection also may be classified according to pathophysiologic changes (cellular-interstitial, vascular, and antibody-endothelial) and severity (extent of histologic inflammation and injury), and may be scored and graded by consensus definitions and arbitrary thresholds of the diagnostic Banff working classification.3,4

Acute cellular rejection (ACR), the most common form of acute allograft rejection, is characterized by mononuclear cell infiltrates in the allograft. The primary Banff lesions of ACR include interstitial inflammation, tubulitis, and intimal arteritis. Borderline change and T-cell–mediated rejection are 2 ACR categories defined in the Banff classification, with T-cell–mediated rejection further subdivided into T-cell–mediated rejection I (interstitial rejection) and T-cell–mediated rejection II/III (vascular rejection).3 The histologic features may reflect the severity of allograft rejection, and the number and severity of acute rejection episodes may affect the choice of therapy and long-term graft survival.5-8 However, the timing of acute rejection is important in determining renal graft outcome. The Banff criteria may be suitable for the evaluation of early rejection, with most biopsies showing little scarring. However, there is controversy about whether the diagnostic criteria apply to late-onset ACR because late-onset ACR often is difficult to reverse and has a high risk of subsequent graft loss.9,10

The description of each rejection category has evolved because of new research, and more areas are being investigated for further clarification. The criteria for C4d-negative antibody-mediated rejection, which histologically is characterized by microcirculation injury in the presence of donor-specific alloantibodies, currently is being validated by a Banff working group.

The purpose of this study was to evaluate patients who had ACR, but who were negative for donor-specific antibodies, C4d, or microcirculation injury. We evaluated (1) whether the pathologic profiles of early and late ACR were associated with a specific graft outcome and (2) which specific lesions using the current scoring system may predict long-term graft failure. The threshold for biopsy may differ between centers; therefore, the present study focused on our homogeneous population of kidney transplant recipients, which was a setting with a clearly defined biopsy strategy to test the prognostic value of the Banff categorization.

Materials and Methods

Patient and data collection
From January 1, 1996 to December 31, 2010, there were 1083 adult patients (≥ 18 years) who received a deceased-donor or living-related single kidney transplant and had follow-up > 6 months at our center. After excluding 836 patients (Figure 1), there were 247 patients enrolled in this retrospective study who had ≥ 1 episode of ACR. We defined that borderline, T-cell–mediated rejection I, and T-cell–mediated rejection II/III represented low, middle, and high ACR severity in this study. For each patient, only the biopsy showing highest ACR severity was evaluated. Therefore, 247 biopsies (1 biopsy/patient) were evaluated and separated into early ACR (timing of biopsy ≤ 6 mo after transplant) and late ACR (biopsy > 6 mo after transplant), and the pathologic features of early and late biopsy-proven acute rejection were studied separately. Delayed graft function was determined by the need for dialysis within 1 week after kidney transplant.11 Death-censored graft failure was defined as the outcome when the patient resumed chronic dialysis. All clinical and laboratory data were recorded in our transplant database system at each visit. The study was approved by the Ethical Review Committee of the institute. All protocols conformed with the ethical guidelines of the 1975 Helsinki Declaration. Informed consent was obtained from all subjects.

Pathology
An ultrasonography-guided graft biopsy was performed when clinically indicated from the serum creatinine level. All patients who had delayed graft function had a protocol biopsy at day 7 after kidney transplant. The specimens were processed at the Department of Pathology, Charité Campus Mitte. An adequate sample was defined by ≥ 7 glomeruli and 1 artery. Indirect immunofluorescence staining of C4d was performed on paraffin sections (polyclonal anti-C4d antibody, Dianova, Hamburg, Germany). For biopsies that had been taken before the availability of C4d testing, the biopsies were tested retrospectively for C4d. Diffuse linear C4d deposition was interpreted as positive. All light microscopy slides were reviewed by 2 pathologists (BR and KW) and graded according to the 2009 Banff classification.12 Each sample was scored on the following: glomerulitis, peritubular capillaritis, transplant glomerulopathy, intimal arteritis, interstitial inflammation, tubulitis, mesangial matrix increase, vascular intimal fibrosis, arteriolar hyaline thickening, and interstitial fibrosis/tubular atrophy. To evaluate the extent of glomerular sclerosis, we counted the number of sclerotic glomeruli in all glomeruli in the biopsy and classified the percentage of glomerular sclerosis into 4 grades (glomerular sclerosis 0, [0%-5%,]; 1­,­­ [6%-25%]; 2, [26%-50%]; 3, [> 50%]). When C4d and donor-specific antibodies were negative, borderline was defined by histologic indices tubulitis 1/interstitial inflammation 1-2 or interstitial inflammation 1/tubulitis 1-2; T-cell–mediated rejection I was defined by intimal arteritis 0, tubulitis 2-3, and interstitial inflammation 2-3; and T-cell–mediated rejection II/III defined as intimal arteritis 1-3, tubulitis 0-3, and interstitial inflammation 0-3.13 The microcirculation injury lesions included glomerulitis ≥ 1; peritubular capillaritis ≥ 1; or transplant glomerulopathy ≥ 1. The diagnosis of antibody-mediated rejection was based on simultaneous presence of donor-specific antibodies, C4d, and allograft pathology. The biopsies that satisfied criteria for antibody-mediated rejection and had tubulitis or intimal arteritis were defined as mixed antibody-mediated rejection plus ACR. The C4d-negative antibody-mediated rejection was considered when C4d was negative but donor-specific antibodies and morphologic microcirculation injury were present.

Human leukocyte antigen antibody screening
Donor-specific antibody level was monitored as previously described.14 All serum samples that were collected annually or at biopsy were qualitatively screened for human leukocyte antigen antibodies by 2 screening systems that were based on enzyme-linked immunosorbent assay: from 1996 to 2006, we used an enzyme-linked immunosorbent assay test with soluble human leukocyte antigen class I molecules as targets (PRA-STAT, Sangstat, Fremont, CA, USA) and linker for activation of T cells; after 2006, we used a bead assay (Luminex-based, LABScreen Mixed, One Lambda, Canoga Park, CA, USA). All tests were performed according to guidelines from the manufacturers.15

Immunosuppressive protocol and antirejection treatment
The immunosuppression protocol included cyclo-sporine/tacrolimus, mycophenolate mofetil/aza-thioprine, and methylprednisolone after 1996. The doses of cyclosporine and tacrolimus were adjusted according to whole blood trough levels. Antirejection therapy involved 2 steps: (1) pulse therapy with corticosteroids or (2) patients who had steroidresistant ACR received antibody therapy (antithymocyte globulin or rituximab) and additional therapeutic plasmapheresis. Complete, partial, and nonreversible ACR were defined by comparing the serum creatinine level at 1 month after biopsy with the prebiopsy level, as previously described.16

Statistical analyses
Data analyses were performed with statistical software (SPSS for Windows, Version 16.0, SPSS Inc., Chicago, IL, USA). All data were assessed for completeness by 1 investigator (DS). Continuous variables were expressed as mean ± standard deviation. Categorical variables were expressed as number (%). Compa-risons were evaluated with the t test for 2 groups of continuous variables and the chi-square test for categorical data. Survival curves were analyzed by Kaplan-Meier method and compared with log-rank test. To evaluate putative risk factors for long-term graft loss, clinical and histologic features were tested in univariate analysis with Cox proportional hazards regression model; variables that were significant (P ≤ .05) were entered into multivariate analysis. Statistical significance was defined by P ≤ .05.

Results

Study population
In the 247 patients enrolled in the study, 92 patients had 1 episode of ACR and 155 patients had multiple episodes of ACR. The ACR episodes that represented the highest severity for each patient were classified into 3 groups: borderline (81 patients [33%]), T-cell–mediated rejection I (103 patients [42%]), and T-cell–mediated rejection II/III (63 patients [25%]). In addition, 189 patients (77%) had biopsies performed during ≤ 6 months after kidney transplant, meeting the definition of early ACR (borderline, 65 patients; T-cell–mediated rejection I, 71 patients; T-cell–mediated rejection II/III, 53 patients).

Demographics and clinical characteristics
The recipient characteristics and clinical course after transplant were similar in patients who had early or late ACR, except high peak panel reactive antibody was significantly more frequent in patients who had late than early ACR (Table 1).

The ACR developed at median 12 days after transplant (all patients), significantly earlier in patients who had early than late ACR (Table 2). All patients had from 1 to 8 biopsies as clinically indicated and experienced 1 to 6 episodes of ACR, and the late ACR group had significantly more biopsies and ACR episodes than the early ACR group (Table 2). The mean serum creatinine level before, at, and 1 month after biopsy was significantly higher in patients who had early than late ACR (Table 2). For patients who had similar severity of rejection (borderline, T-cell–mediated I, or T-cell–mediated II/III), the frequency of response to antirejection therapy was similar in patients who had early or late ACR (Table 2).

Histologic evaluation of biopsies
Compared with patients who had early ACR, patients who had late ACR had significantly higher scores for arteriolar hyaline thickening, interstitial fibrosis/tubular atrophy, interstitial inflammation, tubulitis, and vascular intimal fibrosis (Table 3). The mean interstitial fibrosis/tubular atrophy score was greater for late than early borderline patients. The mean arteriolar hyaline thickening and interstitial fibrosis/tubular atrophy scores were greater for late than early T-cell–mediated rejection I. The arteriolar hyaline thickening, interstitial fibrosis/tubular atrophy, mean mesangial matrix increase, tubulitis, and vascular intimal fibrosis scores were greater for late than early T-cell–mediated rejection II/III. In early ACR, the mean interstitial inflammation and tubulitis scores were significantly greater for the T-cell–mediated rejection I than either early borderline or T-cell–mediated rejection II/III groups. In late ACR, the mean interstitial inflammation and tubulitis scores were significantly greater for borderline than either T-cell–mediated rejection I or T-cell–mediated rejection II/III. In late ACR, the mean vascular intimal fibrosis score was significantly greater for T-cell–mediated rejection II/III than either borderline or T-cell–mediated rejection I, and the mean interstitial fibrosis/tubular atrophy score was greater for T-cell–mediated rejection I or II/III than borderline patients (Table 3).

Long-term graft outcomes in early and late ACR groups
There were 43 patients (early ACR, 23 patients; late ACR, 20 patients) who resumed chronic dialysis (Table 4). Death-censored graft survival at 1 year after kidney transplant was similar between the early ACR (98%) and late ACR groups (98%: not significant), but graft survival at 5 and 8 years after kidney transplant was significantly greater for the early ACR (5 y, 96%; 8 y, 88%) than late ACR group (5 y, 83% [P ≤ .002]; 8 y, 66% [P ≤ .001]). Between the 3 ACR groups of different severity, death-censored graft survival was comparable between early and late T-cell–mediated rejection I at 1, 5, and 8 years after kidney transplant; early borderline and T-cell–mediated rejection II/III had statistically higher death-censored graft survival than late borderline and T-cell–mediated rejection II/III at 5 and 8 years after kidney transplant; and late T-cell–mediated rejection II/III had the lowest death-censored graft survival of any subset (30%) (Table 4). In both early and late ACR groups, graft survival was significantly lower for the T-cell–mediated rejection II/III than borderline group, and there was no significant difference between the borderline and T-cell–mediated rejection I groups (Table 4, Figure 2).

High-grade interstitial fibrosis and tubular atrophy (grade, 2-3) was observed in 20 biopsies (early ACR, 4 patients; late ACR, 16 patients), and the other 227 biopsies had only low grade lesions (grade, 0-1) (Table 4). However, regardless of the timing of ACR, the grafts with low- or high-grade interstitial fibrosis and tubular atrophy had similar death-censored graft survival (Table 4).

High-grade vascular intimal fibrosis (grades 2-3) was noted in 94 biopsies (early ACR, 69 patients; late ACR, 25 patients), and the other 153 biopsies had low grade vascular intimal fibrosis (grades 0-1) (Table 4). In biopsies that showed vascular intimal fibrosis grade 2-3, survival was significantly higher in early than late ACR groups (Table 4). In the late ACR group, the death-censored graft survival was greater in patients who had vascular intimal fibrosis grades 0-1 than grades 2-3 (Table 4).

Intimal arteritis was observed in 63 biopsies (grade 1 [mild], 40 biopsies; grades 2-3 [higher], 23 biopsies (Table 4). The grafts with mild intimal arteritis (grade 1) had significantly higher survival in grafts that had early than late ACR (Table 4). No significant differences in graft and patient survival were noted between low- and high-grade intimal arteritis.

Association of Banff scored lesions and clinical features with long-term graft failure
In all patients, univariate analysis showed several features associated with death-censored graft failure at 8 years after kidney transplant (Table 5); multivariate analysis showed that ACR reversibility, number of biopsy episodes, and intimal arteritis were independent predictors of graft loss at 8 years after kidney transplant (Table 6). Multivariate analysis also showed that number of biopsy episodes, intimal arteritis, and tubulitis were associated with graft loss in the early ACR group, and vascular intimal fibrosis was the only risk factor associated with graft loss in the late ACR group. The timing of biopsy and interstitial fibrosis/tubular atrophy were not associated with long-term graft loss.

Discussion

We retrospectively studied 247 biopsies that showed the highest ACR severity of each patient (247 patients) and were negative for donor-specific antibodies, C4d, or microcirculation injury-lesions. We showed that patients who had late-onset ACR had poorer long-term graft survival than patients who had early-onset ACR. The pathologic features of early- and late-onset ACR were analyzed: (1) the responses to antirejection therapy were similar between early- and late-onset ACR in all patients and in each ACR severity group; (2) the numbers of clinically indicated biopsies, intimal arteritis, and tubulitis were associated with long-term graft loss in the early ACR group; (3) high grade vascular intimal fibrosis was associated with long-term graft loss in the late ACR group.

In all Banff scored lesions, the inflammatory lesions (intimal arteritis, interstitial inflammation, and tubulitis) were the basic diagnostic thresholds for ACR, represented ACR severity, and were associated with response to corticosteroids and/or other antirejection drugs.17,18 Interstitial inflammation and tubulitis alone have the greatest likelihood of reversibility and good graft outcome, and intimal arteritis is less responsive to steroid treatment and may require potent antibody therapy, especially for transmural arteritis and/or arterial fibrinoid necrosis.19,20 Incompletely reversible ACR may cause more clinically indicated biopsies and increase the risk of late rejection, both of which may cause persistent and progressive parenchymal damage and graft failure.21,22 In our study, the proportion of incomplete response (partial reversibility or nonreversibility) to antirejection treatment was comparable between early and late interstitial rejection (borderline and T-cell–mediated rejection I) and between early and late vascular rejection (T-cell–mediated rejection II/III). Both intimal arteritis and tubulitis had significant association with long-term graft failure. There was no significant difference in graft survival between early T-cell–mediated rejection I and early T-cell–mediated rejection II/III groups. These data were in accordance with a recent study that reported that, compared with acute cellular interstitial rejection, the risk of graft loss was 9.07-fold higher in antibody-mediated rejection with intimal arteritis, 2.93-fold higher in antibody-mediated rejection without intimal arteritis, and not significantly different in acute cellular vascular rejection.23

However, the graft outcome may not be similar between interstitial rejection or vascular rejection. The progression to graft failure occurred more frequently in patients who had late T-cell–mediated rejection II/III than late T-cell–mediated rejection I. The poor prognosis of late T-cell–mediated rejection II/III likely is associated with unrecognized antibody-mediated rejection because end-stage human kidney transplant rejection with severe T-cell–mediated rejection usually has concomitant antibody-mediated rejection.24,25 To minimize any possible effect of antibody-mediated rejection, we excluded any biopsies that were positive for C4d, donor-specific antibodies, or microcirculation injury. Nevertheless, we cannot completely exclude the mixture of ACR with chronic active antibody-mediated rejection because we did not routinely check for antibody-mediated rejection (multilayered peritubular capillary basement membranes, electron microscopy, C4d negative antibody-mediated rejection tested by C1q-fixed donor-specific antibodies, or nonhuman leukocyte antigen antibodies).26,27

Aside from the 3 inflammatory lesions, late ACR may have a higher risk of subsequent graft loss than early ACR because of higher scores of tubulointerstitial scarring (interstitial fibrosis/tubular atrophy) and vascular diseases (arteriolar hyaline thickening or vascular intimal fibrosis). Interstitial fibrosis/tubular atrophy is common in late allografts and indicates the cumulative burden of injury and diseases.5 However, interstitial fibrosis/tubular atrophy is not a disease itself, but a feature of all progressive kidney diseases. Early interstitial fibrosis/tubular atrophy has an immune basis and indicates subclinical rejection, tubulointerstitial disease, and the residua of previous episodes of clinically evident acute rejection. Later interstitial fibrosis/tubular atrophy, combined with progressive vasculopathy and glomerulosclerosis, may be accelerated by nonimmune events such as polyoma nephropathy and recurrent pyelonephritis.28 The presence of isolated interstitial fibrosis/tubular atrophy is weakly associated with outcome; however, some lesions such as transplant vasculopathy, subclinical rejection, or transplant glomerulopathy are associated with poor graft survival when they also are associated with interstitial fibrosis/tubular atrophy.29,30 In our study, although progressive interstitial fibrosis/tubular atrophy was present in grafts with late ACR, the mean interstitial fibrosis/tubular atrophy grade of late ACR had not advanced to the chronic scarring stage. Therefore, the contribution of interstitial fibrosis/tubular atrophy to distinct graft outcomes in early and late ACR was minimal.

Graft survival was higher in grafts that had low- than high-grade vascular intimal fibrosis, and the grafts with late ACR and high-grade vascular intimal fibrosis had the poorest long-term graft survival. In contrast, no significant difference was observed between early and late ACR with low-grade vascular intimal fibrosis. Vascular intimal fibrosis is a hallmark of chronic allograft dysfunction affecting transplanted allografts in the long term and contributes to late graft loss.31 Transplant arterio-sclerosis is a multifactorial process, and many risk factors have been identified. Long-term exposure to calcineurin inhibitors is a major risk factor for vascular intimal fibrosis and can induce arterial intimal fibroproliferation and neointimal thickening; this may progress to obliterative vasculopathy, with luminal narrowing that may cause graft ischemia and striped tubulointerstitial fibrosis.32 In addition, some histologic characteristics of vascular rejection, including endothelial-cell apoptosis and the synthesis of matrix proteins and collagens by intimal myofibroblasts, increase the development of arterio-sclerosis.33 Patients in the T-cell–mediated rejection II/III group had more intensive immunosuppression because of concerns about incomplete reversibility; therefore, later in the course, the mean grade of vascular intimal fibrosis was higher in the late than early T-cell–mediated rejection II/III group. In contrast, late and early borderline and T-cell–mediated rejection I groups maintained a low grade of vascular intimal fibrosis.

In conclusion, kidney transplant grafts that had the same severity of ACR had similar reversibility regardless of the timing of biopsy. Increased numbers of clinically indicated biopsies predicted poorer long-term graft survival. Early and late ACR had different pathologic phenotypes, each associated with a distinct long-term graft outcome. Interstitial fibrosis/tubular atrophy, intimal arteritis, and tubulitis independently affected long-term allograft dysfunction in early-onset ACR. In contrast, high-grade vascular intimal fibrosis was a risk factor for poor long-term graft survival in late-onset ACR.


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Volume : 12
Issue : 4
Pages : 314 - 322
DOI : 10.6002/ect.2014.0044


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From the 1Medizinische Klinik mit Schwerpunkt Nephrologie and 2Institut für Pathologie, Charité Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany
Acknowledgements: K. Wu performed the research and wrote the paper. K. Budde and H. H. Neumayer participated in the research design. D. Schmidt participated in data analysis. B. Rudolph participated in evaluation of pathologic tissue, research design, and writing the paper. The authors have no conflicts of interest to disclose, and there was no funding for this study.
Corresponding author: Dr. Birgit Rudolph, Institute of Pathology, Charité Campus Mitte,Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany
Phone: +49 30 450 536 034
Fax: +49 30 450 536 942
E-mail: Birgit.Rudolph@charite.de