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Keywords:

  • Peritubular capillary;
  • rejection;
  • renal transplantation

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

While glomerulitis is graded according to the Banff classification, no criteria for scoring peritubular capillaritis (PTC) have been established. We retrospectively applied PTC-scoring criteria to 688 renal allograft (46 preimplantation, 461 protocol, 181 indication) biopsies.

A total of 26.3% of all analyzed biopsies had peritubular capillaritis (implant 0%, protocol 17.6%, indication 45.5%; p < 0.0001). The most common capillaritis pattern was of moderate severity (5–10 luminal cells), focal in extent (10–50% of PTC), with a minority of neutrophils. A total of 24% of C4d− compared with 75% of C4d+ biopsies showed capillaritis (p < 0.0001). More than 80% of biopsies with glomerulitis had peritubular capillaritis. A total of 50.4% of biopsies with borderline or T-cell mediated rejection (TCMR) and 14.1% of biopsies without TCMR or antibody-mediated rejection (ABMR) showed capillaritis (p < 0.0001). The inter-observer reproducibility of the PTC-scoring features was fair to moderate. Diffuse capillaritis detected in early protocol biopsies had significant negative prognostic impact in terms of glomerular filtration rate2 years posttransplantation. Indication biopsies show a significantly higher prevalence of capillaritis than protocol biopsies (45.5% vs. 17.6%; p < 0.0001). Capillaritis is more frequent and pronounced in ABMR, but can be observed in TCMR cases. Thus, scoring of peritubular capillaritis is feasible and can provide prognostic and diagnostic information in renal allograft biopsies.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

The primary target of circulating antidonor HLA antibodies in the setting of antibody-mediated rejection (ABMR) is the endothelium of the allograft microcirculation i.e. in renal transplants, the glomerular and peritubular capillaries (PTC) (1). Luminal accumulation of inflammatory cells in PTC, i.e. peritubular capillaritis, is a lesion that has been previously associated with ABMR in renal allografts (2–4). Numerous studies have shown that peritubular capillaritis correlates with antidonor HLA class I or II antibody and C4d deposition in PTC, as recently reviewed (5,6). Furthermore, some recent studies have also linked peritubular capillaritis in early allografts with the development of later chronic graft injury (7–9). In particular, Lerut et al. (9) have shown that subclinical peritubular capillaritis at 3 months posttransplant is associated with the development of peritubular capillary basement membrane multilayering at 1 year posttransplant. Sis et al. found peritubular capillaritis in >70% of cases with transplant glomerulopathy and most of these case showed chronic remodeling of PTC with multilayering of their basement membranes (10). In addition, ultrastructural studies on sequential biopsies from patients with ABMR revealed that luminal inflammation in PTC is associated with endothelial cell injury as well as fragmentation of the basement membrane. Follow-up biopsies then showed reparative changes and early onset of transplant capillaropathy and glomerulopathy, suggesting ongoing endothelial injury induced by peritubular capillaritis as a precursor of chronic rejection (9,11).

Scoring of inflammation in glomeruli (i.e. transplant glomerulitis) is part of the original Banff classification as the ‘Banff g score’ (12), and the presence of polymorphonuclear and/or mononuclear leukocytes in PTC is one of the Banff criteria for the diagnosis of ABMR (13). However, no defined scoring schema for peritubular capillaritis (i.e. PTC score) has yet been established. Peritubular capillaritis shows variation in extent (proportion of capillaries involved), severity (number of leucocytes per capillary), and type (polymorphonuclear and/or mononuclear leukocytes) but it is not clear whether these variables are of diagnostic significance. In the past, neutrophil polymorphs (PMNLs) in particular have been associated with ABMR (14,15), but more recent studies have shown that mononuclear cells can be the predominant and possibly pathogenetically more relevant cell population in C4d+ cases of ABMR (16). Therefore, the assessment of peritubular capillary inflammation must take into account not just the absolute number (i.e. quantity) of inflammatory cells, but also the composition (i.e. quality) of cells.

At recent Banff Conferences on Allograft Pathology (2003 and 2005), one of us (IWG) proposed a scoring system for PTC inflammation, which has been published in the Banff 2005 meeting report (17). This PTC scoring system (i.e. PTC score) was not formally included into the Banff classification schema, pending more data concerning reproducibility and diagnostic relevance of this feature. Therefore, we retrospectively applied the proposed PTC score to 688 renal allograft biopsies. Results were compared to C4d staining and glomerulitis as established Banff lesions of ABMR and to the diagnosis of T-cell mediated rejection (TCMR). In a subset of indication biopsies, peritubular capillaritis was correlated to graft function. Intra- and interobserver reproducibility was evaluated among six renal transplant pathologists.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Initial proposal for scoring peritubular capillaritis (PTC score)

The proposed quantitative thresholds for scoring peritubular capillaritis were as follows: no significant cortical peritubular inflammation (0–2 luminal inflammatory cells; PTC 0), cortical peritubular capillary with 3–4 luminal inflammatory cells (PTC 1, Figure 1A), with 5–10 luminal inflammatory cells (PTC 2, Figure 1B), and with >10 luminal inflammatory cells (PTC 3, Figure 1C and D). The PTC score should be based on the highest number of all types of luminal inflammatory cells, and the cell composition (PTC quality) should also be indicated, i.e. presence of mononuclear cells only with an * (Figure 1A), and the proportion of PMNLs, ≤50% (Figures 1B and C) versus >50% (Figure 1D) of intraluminal cells. The extent of the lesion (PTC extent) should be stated as focal (≤50% of PTC involved) or diffuse (>50% of PTC involved) and the presence of associated PTC dilatation could also be noted. It was proposed that certain areas of biopsies (listed in Table 1) should be avoided for PTC scoring.

image

Figure 1. Example of the three PTC capillaritis scores (Silver (A) and PAS (B–D) stain at 600× magnification). (A) shows capillaritis with a PTC-score 1*, i.e. 3–4 luminal inflammatory cells. The (*) indicates a mononuclear only composition of the capillaritis. (B) shows capillaritis with a PTC-score 2, i.e. 5–10 luminal inflammatory cells. Neutrophils are <50% of the luminal cells. (C) shows capillaritis with a PTC-score 3, i.e. >10 luminal inflammatory cells. Neutrophils are <50% of the luminal cells. (D) shows capillaritis with a PTC-score 3, but this time neutrophils are the dominating cell type (>50%) within the luminal cells.

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Table 1.  Avoid scoring of peritubular capillaritis in
• Medulla
• Subcapsular cortex
• Areas of pyelonephritis
• Areas of necrosis/infarction
• Vessels immediately surrounding nodular lymphoid aggregates
• Vessels cut in an obviously longitudinal section

Biopsies and study design

We retrospectively applied the initially proposed PTC-scoring schema to 688 renal allograft biopsies from University of Manitoba (biopsies evaluated by IWG) and Hannover Medical School (biopsies evaluated by MM). The series comprised 46 preimplantation biopsies, 461 protocol biopsies (i.e. biopsies taken at predetermined time points [≤12 months] after transplantation independent of the actual allograft function) and 181 indication biopsies (from patients with clinically overt allograft dysfunction). Biopsies were selected by a retrospective database search in both centers from the years 2004 and 2005 and were included when C4d staining results and histochemically stained slides were readily available. The PTC-score, quality, extent and dilatation were compared to established Banff scores and C4d-status. C4d staining of paraffin sections (biopsies from Hannover) was evaluated as negative (<25% of PTC with specific circumferential C4d stain), focal positive (25–50% PTC stained) or diffuse positive (>50% PTC stained). In frozen section (biopsies from Winnipeg) also >50% PTC stained was the threshold for diffuse C4d positive, whereas cases with >0–50% PTC stained were called focal positive.

Peritubular capillaritis and allograft function

In 78 indication biopsies peritubular capillaritis was correlated to the serum creatinine values at the time point of biopsy. For a subset of patients (n = 17 with 55 biopsies), who only had protocol biopsies (taken within the first 6 months after transplantation) but no indication biopsies, 2-year clinical follow-up was available as estimated glomerular filtration rate (eGFR by Cockcroft Gault equation [18]). We only included these patients for outcome analysis to exclude bias by additional indication biopsies with other pathologies. For assessment of future allograft function, the delta eGFR was calculated according to the following equation: [(eGFR 2 year after transplantation – best eGFR within the first 6 weeks after transplantation)/best eGFR within the first 6 weeks after transplantation]× 100%. For outcome analysis in these 17 patients all protocol biopsies within the first 6 months after transplantation were considered, whereas the PTC-scoring categories were collapsed into absent and present calls with the purpose to achieve statistical power.

Intra- and Interobserver reproducibility

Since reproducibility is an issue with all semiquantitative scoring systems, we conducted two reproducibility trials. In a first pilot trial, three observers (IWG, MM and one trainee pathologist, VB) tested the intra- and inter-observer reproducibility of the initially proposed PTC-scoring criteria. For this purpose, 100 biopsies (50 protocol and 50 indication biopsies, 25 of each from each centre) were randomly selected. One PAS-stained slide per biopsy was circulated two times between the three observers and evaluated for PTC-score, quality, extent and dilatation.

Based on the findings of this pilot trial and against the background that the three participants of the pilot trial have either trained together or extensively discussed the scoring criteria, a second larger reproducibility study including nonbiased pathologists was subsequently conducted. For this second study, the same 100 slides were circulated two-times between four renal transplant pathologists (IWG, BS, IR, MM) and two trainee renal pathologists (VB, JR). Amended guidelines for scoring peritubular capillaritis, updated following the pilot study, were circulated to the pathologists along with the slides.

Statistics

The data was analyzed using the SPSS statistical software package, version 15.0 (SPSS Inc., Chicago, IL). Comparisons of categorical data between C4d, the Banff features and different capillaritis features in protocol and indication biopsies were performed with the chi-square test and Fischer's exact test. For serum creatinine comparisons the Kruskal-Wallis test and for delta eGFR comparisons the Mann-Whitney U-test was applied. The p-values <0.05 were considered to be significant. The results of the reproducibility trials were analyzed using weighted kappa statistics (19,20) with the following thresholds: <0.20 = poor, 0.21–0.40 = fair, 0.41–0.60 = moderate, 0.61–0.80 = good, >0.80 = excellent reproducibility. The weighted kappa was computed by using STATA software.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Prevalence and pattern of capillaritis

A total of 26.3% of all analyzed biopsies showed peritubular capillaritis. No capillaritis was seen in preimplantation biopsies. Indication biopsies showed a significantly higher prevalence of capillaritis (45.5%) compared to protocol biopsies (17.6%: p < 0.0001). In only 3.4% of the biopsies (protocol 2.2%, indication 6.1%) capillaritis was severe, with >10 intraluminal inflammatory cells (PTC 3). Less severe capillaritis (PTC 1 and 2) was equally frequent in the respective biopsy groups. No significant differences concerning quality, extent or morphology of capillaritis were seen between protocol and indication biopsies. In only 8% of biopsies with capillaritis were PMNLs the predominant inflammatory cell type. Capillaritis was focal in extent, affecting <50% of PTC in >80% of biopsies, whereas dilatation of PTCs was seen in 50% of biopsies with capillaritis.

Capillaritis and allograft function

For a subset of 78/181 indication biopsies, creatinine values at the time point of biopsy were available: biopsies with PTC 0 score (n = 47) had a mean serum creatinine value of 213 ± 122 μm/l, with PTC 1 score (n = 11) of 246 ± 84 μm/l, with PTC 2 score (n = 16) of 270 ±116 μm/l and with PTC 3 score (n = 4) of 194 ± 120 μm/l (p > 0.05). We then compared patients with any capillaritis in at least one of their protocol biopsies to those without capillaritis in any of their protocol biopsies in regard to the delta in eGFR at 2 years after transplantation. Similarly, those patients with different qualities of capillaritis and different extent of capillaritis (focal or diffuse) in at least one of their protocol biopsies were compared to those who never showed the respective lesion.

This subgroup analysis revealed for the PTC score and for PTC morphology no significant differences, but for PTC extent a significant loss in eGFR with diffuse capillaritis: delta eGFR in patients never showing diffuse capillaritis +6% versus delta eGFR in patients with at least one biopsy with diffuse capillaritis −32%, p = 0.017.

Capillaritis and C4d status

A total of 24.3% of C4d− biopsies (n = 412) showed capillaritis, whereas 68.6% of focal C4d+ (n = 35) and 88.2% of diffuse C4d+ (n = 17) biopsies (p < 0.0001) had capillaritis. The most frequent capillaritis pattern with C4d+ cases (focal and diffuse) was PTC-score 2, with a minority of PMNLs, focal in extent and with equal presence or absence of dilatation (Figures 2A–D). Diffuse C4d+ biopsies comprised the majority of severe capillaritis (PTC 3) cases (diffuse C4d+ 23.5% vs. focal C4d+ 2.9% vs. C4d− 2.7%; p < 0.0001), with >50% PMNLs (diffuse C4d+ 23.5% vs. focal C4d+ 2.9% vs. C4d− 4.4%; p < 0.0001), diffuse extent of capillaritis (diffuse C4d+ 29.4% vs. focal C4d+ 8.6% vs. C4d− 4.4%; p < 0.0001) and with dilatation of PTC (diffuse C4d+ 58.8% vs. focal C4d+ 42.9% vs. C4d− 13.8%; p > 0.05). However, in diffuse C4d+ cases, exclusively mononuclear infiltrates were equally common (23.5%) as predominant PMNL infiltrates (Figure 2B).

image

Figure 2. Peritubular capillaritis and C4d. The percentage and degree of C4d negative, focal C4d positive and diffuse C4d positive biopsies showing the four different features of peritubular capillaritis is given.

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Capillaritis and glomerulitis

We found correlation between peritubular capillaritis and presence of glomerulitis. Only 20% of biopsies with a Banff g0 score had some degree of peritubular capillaritis, compared to 82.8% of biopsies with glomerulitis (p < 0.0001, Figure 3A). The majority of biopsies with glomerulitis and capillaritis were of PTC-score 2 (Figure 3A), with a minority of PMNLs (Figure 3B), a capillaritis which was focal in distribution (Figure 3C) and more commonly with PTC dilatation (Figure 3D).

image

Figure 3. Peritubular capillaritis and glomerulitis. The percentage and degree of biopsies with and without glomerulitis showing the four different features of peritubular capillaritis is given.

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Capillaritis and TCMR

A total of 14.1% of biopsies without any signs of TCMR (below Banff borderline, n = 453) showed capillaritis, compared to 45.7% of borderline (n = 105) and 68.4% of TCMR (at least Banff grade IA, n = 76) cases (p < 0.0001). All grades of capillaritis were found, but the most frequent capillaritis pattern in TCMR cases was PTC-score 2, <50% PMNLs, focal distribution and absence of dilatation of PTC.

Reproducibility and refinement of capillaritis scoring

The pilot study with the three pathologists revealed mean kappa-values for intraobserver reproducibility for the PTC score of 0.62 (good), for PTC quality of 0.48 (moderate), for PTC extent of 0.53 (moderate) and for PTC morphology of 0.37 (fair). Mean kappa-values for interobserver reproducibility were lower with 0.49 (moderate) for the PTC score, 0.39 (fair) for PTC quality, 0.47 (moderate) for PTC extent and 0.30 (fair) for PTC morphology. Since the assessment of PTC morphology (no dilatation vs. dilatation) was difficult to rigorously define, and showed no clear association with other diagnostic features like C4d, glomerulitis or TCMR, we decided to delete this feature from the PTC-scoring schema for the larger reproducibility study. Furthermore, during scoring the biopsies it became apparent that capillaritis could be present very focally, perhaps in only a single PTC. The clinical relevance of such minimally focal capillaritis was considered to be doubtful. We therefore decided, for practical purposes, that minimally focal capillaritis in ≤10% of PTC should be scored as PTC 0 in the larger reproducibility study. Thus, only an occasional PTC with inflammation of any amount was scored as PTC 0.

These findings from the first large-scale application of scoring peritubular capillaritis led to the revised PTC-scoring schema, as shown in Tables 1 and 2. This was then applied in the larger reproducibility study by six pathologists, results of which are shown in Table 3. With the revised PTC-scoring schema, the mean-weighted kappa-values for intraobserver reproducibility slightly improved compared to the pilot trial and were in a moderate-good range (0.59–0.64). For interobserver reproducibility, there wasn't any major outlier in the group of six pathologists, with fair-moderate range kappa values (0.32–0.43).

Table 2.  Revised criteria for scoring peritubular capillaritis
  1. Comments on composition (only mononuclear cells, ≤50% neutrophils, >50% neutrophils) and extent of lesion (focal (10–50% of PTC involved) or diffuse (>50% of PTC involved) should be given in the report.

PTC 0No significant cortical peritubular capillaritis (<3 luminal inflammatory cells) or ≤10% of PTCs with inflammation
PTC 1>10% of cortical peritubular capillaries with capillaritis, with max 3–4 luminal inflammatory cells
PTC 2>10% of cortical peritubular capillaries with capillaritis, with max 5–10 luminal inflammatory cells
PTC 3>10% of cortical peritubular capillaries with capillaritis, with max >10 luminal inflammatory cells
Table 3.  Reproducibility of peritubular capillaritis scoring with six patholgists
 Intraobserver reproducibilityInterobserver reproducibility
MinMaxMeanKappa categoryMinMaxMeanKappa category
PTC score0.470.870.64Good0.280.530.43Moderate
PTC quality0.370.760.59Moderate0.150.450.32Fair
PTC extent0.440.830.63Good0.140.600.38Fair

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Our findings show that scoring peritubular capillaritis is applicable to routine biopsy interpretation and is of diagnostic utility. The finding that indication biopsies have a significantly higher prevalence of capillaritis than protocol biopsies suggests that this morphological feature is related to allograft pathology. There are numerous studies indicating a poor prognostic relevance for the detection of capillaritis (7–11,16,21,22), including a growing body of evidence that capillaritis is a sign of impending chronic rejection, with transplant glomerulopathy and capillaropathy in follow-up biopsies (7,8,9,11). These latter lesions have been identified as strong negative prognostic predictors in renal allografts (23). Outcome analysis in our series was limited by the high percentage of protocol biopsies from stable allografts with lower prevalence of capillaritis and the fact that virtually all patients had several biopsies. Nevertheless patient-related and protocol biopsy-restricted outcome analysis revealed diffuse capillaritis to potentially have negative impact on future allograft function.

We did not find peritubular capillaritis to be pathognomonic for a specific rejection diagnosis, but it was more frequently associated with morphological features being considered to be more diagnostic of ABMR than of TCMR like glomerulitis and C4d detection. We found an overlap of capillaritis with >80% of biopsies showing glomerulitis and/or C4d. But, it has to be noted that glomerulitis can be seen in TCMR as well, and that ABMR cases can be C4d−, as shown by Magil (24). Furthermore, our data concerning C4d might be hampered by the lack of uniform criteria for scoring focal C4d and sensitivity issues between frozen and paraffin section, although recent methodological studies allow for a reasonable comparison of results obtained by both techniques (25). However, the association with ABMR features (i.e. glomerulitis and diffuse C4d) is even more striking when peritubular capillaritis is severe (PTC 3) and diffuse in extent, but the capillaritis in ABMR cases can be either dominated by neutrophils, have a minority component of PMNLs or show a pure monocytic inflammation. The pathophysiologic implications of pure monocytic versus predominant neutrophilic capillaritis still need to be elucidated. Recently Fahim et al. demonstrated that a higher monocyte/T-cell ratio discriminates C4d+ from C4d− cases (16). In addition, recent data suggest that cases of ABMR with PMNL-predominant capillaritis have an inferior outcome compared to ABMR cases without capillaritis (22). Thus, not only reporting the degree and extent of capillaritis, but also the quality of cellular composition of capillaritis, can provide relevant diagnostic and potentially prognostic information.

Scoring of peritubular capillaritis should be restricted to the cortex, since inflammatory cell accumulation in medullary vasa recta can be related to acute tubular necrosis (ATN) (26). Recent studies have shown the existence of lymphatic vessel neoangiogenesis in association with nodular lymphoid cell aggregates in renal allografts (27). Scoring of vessels immediately surrounding such nodular lymphoid aggregates therefore holds the possibility of confusion of PTC and lymphatic vessels, and should therefore also not be taken into account for the PTC score. Furthermore, due to the obvious lack of specificity for allograft rejection, it is not meaningful to consider capillaritis in the immediate vicinity of the organ capsule, and in areas of pyelonephritis, necrosis or infarction, for the PTC score. However, in cases with diffuse interstitial infiltrates (i.e. severe TCMR) it might be impossible to score capillaritis without highlighting the PTC by immunohistochemistry (e.g. CD31 stain) (16).

To become part of routine diagnostic practice, a scoring schema has not only to be feasible but also reproducible. As requested by participants of previous Banff meetings, we conducted a larger reproducibility trial, which included pathologists who had never trained together and who had never before used the refined PTC-scoring schema. This approach ensured realistic conditions for testing the applicability of the schema in daily routine practice. It also explains why the interobserver reproducibility in the larger study was not as good as in the initial pilot study. Nevertheless, we obtained good intraobserver and fair-moderate interobserver reproducibility for the whole PTC-scoring schema, with the PTC score (kappa-value 0.43) being the most reproducible of the three features. Compared to the other established Banff scores, which were tested under comparable conditions by Furness and Taub, we had a better kappa value for inter-observer reproducibility of the PTC score than the values reported for the t- (0.17), i- (0.34) and v-scores (0.35) (28).

In summary, our data demonstrate that peritubular capillaritis is a useful and feasible feature to assess in every renal allograft biopsy. A specific PTC score facilitates careful examination of PTC in renal allograft biopsies. Presenting these data at the 2007 Banff meeting has led to the formal incorporation of the PTC score into the Banff schema, according to the criteria shown in Tables 1 and 2 (29). Consensus about assessing and reporting peritubular capillaritis, analogous to the way that the other acute rejection features (Banff g-, i-, t- and v-scores) are reported, provides the basis for future basic research and clinical trials. These trials are supposed to further elucidate the clinical and prognostic relevance of peritubular capillaritis in various disease states after renal transplantation.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References

Results of the study were presented in abstract form at the World Transplant Congress in Boston, MA in 2006 and at the 9th Banff Conference for Allograft Pathology in La Corunia, Spain in 2007.

Michael Mengel received a research stipend from the Dr. Werner Jackstädt Kidney foundation.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgments
  8. References
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