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NDT Advance Access originally published online on December 8, 2007
Nephrology Dialysis Transplantation 2008 23(5):1735-1741; doi:10.1093/ndt/gfm843
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


The role of C4d immunostaining in the evaluation of the causes of renal allograft dysfunction

Prabhat Ranjan, Ritambhra Nada, Vivekanand Jha*, Vinay Sakhuja* and Kusum Joshi

* Departments of Histopathology and Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India Postgraduate Institute of Medical Education and Research, Chandigarh, India

Correspondence and offprint requests to: Kusum Joshi, Department of Histopathology, PGIMER, Chandigarh-160012, India. Fax: + 91-172-2744401; E-mail: kus_joshi{at}yahoo.com



   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Discussion
 References
 
Background. Renal biopsy is the gold standard for diagnosis of acute rejection in renal transplant recipients. The Banff (1997) classification was revised in 2003 incorporating morphological criteria and C4d immunostaining for the diagnosis of acute antibody-mediated rejection.

Aims. The aim of this study was to evaluate the role of histomorphology and C4d immunostaining in indicated renal allograft biopsies with a clinical follow-up for a minimum duration of 1 year.

Material and methods. Histological analysis and C4d immunostaining were performed on 132 needle core biopsies and 2 nephrectomy specimens from 107 patients from July 2004 to June 2005.

Results. Histological analysis revealed 59 cases of acute rejection, 10 biopsies of acute tubular necrosis, 41 cases of chronic allograft nephropathy (CAN), either alone or in combination with other diseases, and 18 biopsies of normal morphology. There were four cases of BK nephropathy (BK N) and eight cases had miscellaneous diagnoses. C4d immunostaining was performed on 126 biopsies. Overall, the prevalence of C4d positivity was 45% (57 of 126). Fifty-five percent (28 of 51) of the cases of acute rejection showed C4d positivity including 81% of presumptive antibody-mediated rejection (P-AbAR), 20% acute cellular rejection and 58% acute cellular rejection + P-AbAR. Overall C4d positivity was 37% in chronic allograft nephropathy. Acute tubular necrosis and borderline rejection showed 25 and 50% C4d positivity, respectively. Amongst various histological features, capillary margination of polymorphs and dilatation of peritubular capillaries (PTC-D) showed significant association with C4d positivity (P < 0.005). In cases of CAN, transplant glomerulopathy had significant association with C4d positivity. C4d-positive cases had a higher mean value of serum creatinine at the time of biopsies.

Conclusion. It is concluded that C4d staining is a useful adjunct marker of the humoral limb of rejection, both in early and late post-transplant periods.

Keywords: Antibody-mediated rejection; C4d; cellular rejection; renal transplant



   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Discussion
 References
 
Transplant rejection is a complex process in which both cell-mediated immunity and circulating antibodies play a role. Renal biopsy is the gold standard for diagnosis of acute rejection in renal transplant recipients. For the diagnosis of cellular rejection, well-defined histological criteria were laid down under the Banff system in 1993 and were further revised in 1997 [1,2]. Acute humoral rejection may be associated with the appearance of donor-specific antibodies that can be detected using various methods, e.g. panel reactive antibody (PRA) levels, flow cytometry cross match or flow PRA bead assays. But these do not correlate with the morphological as well as immunopathological evidence of humoral rejection [3]. In view of these observations, the Banff (1997) classification was revised in 2003 incorporating morphological criteria, supported by immunopathological criteria, and serological evidence for acute humoral rejection [4].

Acute humoral rejection is mediated by antibodies to the donor endothelium that activate the classical complement pathway. This leads to a number of split products of complement (C3a, C3b, C3d, C4b). C4d is a fragment of C4 released during activation of the classic complement pathway by the antigen–antibody complex. Because C4d contains an internal thioester bond, it binds covalently to tissue elements at the site of activation and is therefore a durable marker of antibody-mediated antidonor humoral response [5]. Detection of C4d is regarded as an indirect sign, a ‘footprint’ of an antibody response.

C4d deposits in peritubular capillaries (PTCs) were first demonstrated by Feucht et al. [7] in biopsies from patients ‘at high immunologic risk’ (high panel reactive antibody) and were associated with poor graft survival. Collin et al. [8] showed a close correlation of PTC C4d staining with concurrent circulating antigen-specific antibody and neutrophils in capillaries (peritubular and glomerular) as well as vascular arterial fibrinoid necrosis [8].

The present study was conducted to evaluate the role of C4d immunostaining in dysfunctional renal allograft biopsies in classifying the type of rejection and to assess its relationship to the severity of graft dysfunction and response to standard antirejection therapy.



   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Discussion
 References
 
This was a prospective study, carried out over a period of 1 year, from July 2004 to June 2005. All indicated renal graft biopsies from renal transplant recipients received during this period in the Department of Histopathology, PGIMER were included.

Clinical data
The following clinical data were analysed and correlated with results:

  1. duration of transplant at the time of biopsy (0–30 days, 31–90 days, 91–180 days, 180–365 days and more than 1 year)
  2. baseline immunosuppressive therapy
  3. therapy after biopsy
  4. graft function was assessed in the form of serum creatinine at the time of biopsy and at the maximum follow-up period.

Histopathological features
A systematic histological analysis of the biopsies was carried out on haematoxylin and eosin-stained and periodic acid-Schiff-stained slides. A careful search was made in each biopsy for features of rejection, and all cases were graded according to Banff (2003) criteria [4]. A meticulous search was made for changes suggestive of antibody-mediated rejection according to Banff (2003). The following morphological diagnostic criteria were used for the presumptive diagnosis of antibody-mediated acute rejection (P-AbAR): (i) acute tubular necrosis (ATN), (ii) peritubular capillary (PTC) margination (neutrophils in PTC, Figure 1), (iii) PTC dilatation (PTC-D, Figure 1), (iv) fibrin thrombi in vessels, (v) glomerulitis (neutrophils in the glomerular capillaries) and (vi) fibrinoid necrosis. Biopsies with more than one of the above-mentioned features and with or without mild tubulitis were categorized as a presumptive diagnosis of AbAR (P-AbAR). Capillary marginations by neutrophils were taken as positive, when they were present in ≥10% of PTC in a non-sclerosed cortex. Biopsies with only features of acute tubular necrosis and no other features of P-AbAR were categorized separately as acute tubular necrosis.


Figure 1
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  		Fig. 1 Peritubular capillary (PTC) margination (neutrophils in PTC) and PTC dilatation (PTC-D).

 
In addition, other features looked for in the biopsies were glomerular disease, including recurrent disease, interstitial changes independent of rejection, like inflammation and fibrosis, drug toxicity (cyclosporine) and infections (bacterial, fungal and viral).

C4d immunostaining
Immunoperoxidase staining was carried out by an avidin-biotin technique. Antigen retrieval was done by a pressure cooker method. Rabbit polyclonal antihuman C4d antibody (C4dAb, Cat.No.B1-RC4D) from Biomedica was used as primary antibody. During standardization of C4d immunostaining, non-graft kidney biopsies diagnosed as minimal change disease, membranous glomerulonephritis and MPGN were used as controls [6]. However, during study only biopsies of minimal change disease were taken as a negative control. Glomerular staining of graft biopsies for C4d did not correlate with any histological features nor diagnostic categories, however, served as an internal quality control. No glomerular staining of C4d was found in control biopsies for C4d.

Biopsies were assessed for C4d immunostaining, without knowledge of histological features or the clinical data. Only non-fibrotic and non-necrotic parenchymal regions were evaluated. C4d deposits in other locations (e.g. glomeruli along with atrophic tubules) were regarded as non-diagnostic. C4d was typically detected along PTCs with a strong linear staining pattern (Figure 2). Scoring was done according to Table 1. As in previous studies, biopsies were labelled C4d positive only when differential staining was seen in ≥25% of PTCs in the cortical area [9].


Figure 2
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  		Fig. 2 C4d was typically detected along peritubular capillaries (PTC) with a strong linear staining pattern.

 

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  		Table 1 Scoring of C4d immunostain

 
Statistical analysis
Comparisons between groups were performed using Pearson's {chi}2 test. P values < 0.05 were reported as statistically significant. A commercially available computer program (SPSS 9.0, SPSS Inc., Chicago, IL, USA) was used for all statistical calculations.



   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Discussion
 References
 
The study material in this prospective study comprised 132 needle core biopsies and 2 nephrectomy specimens from 107 patients. Out of a total of 107 patients, 85 had a single biopsy whereas 18, 3 and 1 had two, three and four sequential biopsies respectively. There were 92 males and 15 females. Nine female patients were married and had more than one child. There was no history of repeated blood transfusions in either group except in two female patients. These two ladies had multiple blood transfusions during childbirth. The age of the patients ranged from 10 to 65 years with a mean of 34 years. All patients except three received live-related kidney transplant. In this study, the PRA or DSA level was not determined. The duration between renal transplant and biopsy varied from 2 to 3720 days (mean 447.7 days). The follow-up period of these patients ranged from 2 to 18 months (mean 8.5 months). Two patients died during the follow-up period due to complications of immunosuppression, and in one patient re-transplantation was done due to graft failure. Baseline maintenance immunosuppresion was cyclosporine, prednisone and azathioprine.

Histopathological evaluation of renal allograft biopsies according to Banff (2003)
There were a total of 59 cases of acute rejection, 10 cases of acute tubular necrosis, 41 cases of CAN, either alone or in combination with other diseases, and 18 biopsies of normal morphology. There were four cases of BK nephropathy (BK N). The diagnosis of BK nephropathy was made on the morphological criteria, mainly anisonucleosis, nuclear smudging, nucleomegaly and intranuclear inclusion of tubular lining epithelium. Eight cases showed miscellaneous changes that included non-specific change (3), mild inflammation (2), thrombotic microangiopathy (1), post-transplant lymphoproliferative disease (1) and scanty tissue (1). The histological diagnoses of 134 cases are tabulated in Table 2.


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  		Table 2 Histopathological diagnoses of graft biopsies (n = 134) and percent of C4d immunostain positivity with histology (n = 126)a

 
Using the criteria laid down by Banff (2003), only one biopsy had acute cellular rejection grade 1 B with CAN and the rest were acute cellular rejection grade 1A. Only 29% of CAN (12/41) were CAN grade 2 and the rest were CAN grade 1. Transplant glomerulopathy and arteriopathy were seen in 21 (51%) and 8 (19.5%) cases of CAN, respectively.

Evaluation of C4d immunostaining
C4d immunostaining was performed on 126 biopsies. Eight paraffin blocks had scanty tissues. C4d staining was detected in a linear fashion along the entire circumference of PTCs (Figure 2). C4d was not found in normal or reactive tubular epithelial cells (in the case of BK nephropathy) or normal tubular basement membranes. The basement membrane of atrophic tubules showed nonspecific, weak C4d positivity. Arteries did not show C4d deposits even in the case of thrombotic microangiopathy or arteriolar hyalinosis.

The overall prevalence of C4d positivity in all renal allograft biopsies was 45% (57 of 126). Eighteen percent (23 of 126) of the biopsies revealed focal (>25%) and 27% (34 of 126) diffuse (>50%) positivity. Further statistical analyses did not reveal differences between focal and diffuse C4d positivity with any histological changes or graft outcome; therefore, all focal and diffuse positive cases were referred as only positive (similar to the approach used by the authors of references [14,15]). C4d positivity was 81% in P-AbAR and only 20% in acute cellular rejection (ACR). Cases of CAN demonstrated 30% positivity for C4d (7 of 23). Two cases of CAN with BK nephropathy showed no positivity for C4d immunostaining. Five out of six cases of CAN with P-AbAR revealed strong C4d positivity (Table 2).

Association between C4d and clinical data
No correlation was noted with any clinical profile of transplant recipients like sex, age, history of blood transfusion and number of pregnancies. However, biopsies from five out of nine married patients showed C4d positivity, and biopsies of the rest of the female patients were negative for C4d.

Association between C4d immunostaining pattern and individual histological features
Individual histological features in 126 biopsies evaluated for C4d immunostaining were correlated with either positive or negative C4d staining. Biopsies were categorized into the C4d positive (n = 57) and C4d negative (n = 69) group (Table 3).


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  		Table 3 Association between the accumulation of C4d and histologic changes in allograft biopsies

 
Acute tubular necrosis, capillary margination of polymorphs, peritubular capillaries dilatation (PTC-D), polymorphs in glomeruli (glomerulitis) and fibrin thrombi in capillaries/vessels were more common in the C4d-positive group. Forty-seven biopsies showed PTC-D; 36 of these had capillary margination. Statistical analysis by the chi-square test revealed a highly significant association of C4d positivity with capillary margination and PTC dilatation with the P value of 0.003 and 0.001 respectively. There was weakly significant correlation with transplant glomerulopathy (P value = 0.05). Peritubular dilatation of capillaries was found in 9/41 cases of CAN, 1/4 cases of pyelonephritis and 2/10 cases of ATN. The rest of the PTC-D were found in the biopsies with diagnoses of acute antibody-mediated rejection, alone or in combination with another diagnosis, including two cases of acute cellular rejection. PTC-D was not found in biopsies when diagnosis was only acute cellular rejection.

Association between C4d and duration after transplant
The histological and C4d status in various biopsies was analysed according to the duration between transplant and the biopsy. On the basis of the duration of transplant, 66% of P-AbAR cases (10 of 15) were seen within 30 days, whereas ACR cases (n = 8) occurred more commonly after 1 month. Larger numbers of C4d-positive cases were seen in the < 30 days group if the histological diagnosis was P-AbAR and in the >365 days group when associated with CAN.

CAN was seen frequently after 1 year. However, CAN was seen even in the first 3 months; in this period 8 of 61 biopsies (13%) were diagnosed as chronic allograft nephropathy, among which 2/8 (25%) were C4d positive.

Follow-up
Estimation of serum creatinine at the time of biopsy and at the maximum follow-up period was done. Serum creatinine at the time of biopsy ranged from of 1.7 mg/dl to the maximum 12.4 mg/dl (mean 3.6). At the maximum follow-up period, the level of serum creatinine ranged from 0.9 to 10.0 mg/dl (mean 2.4 mg/dl). The serum creatinine level at the maximum follow-up period did not reveal any association with the C4d immunostain. However, the mean serum creatinine level at the time of biopsies in the C4d-positive group was higher than that in the C4d negative group.



   Discussion
Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
References
 
The gold standard for the diagnosis of rejection and for guiding patient management of renal transplant recipients is the histological evaluation of a renal allograft biopsy [10]. Over the past decades, no well-defined criteria for the proper identification of humoral rejection episodes in the early or late post-transplantation period have been defined. Hence, antibody-mediated rejection episodes frequently remained undiagnosed and unclassified. Consequently, nearly all acute rejection episodes have been classified as ‘cell mediated’. Currently, C4d is regarded as an immunohistochemical marker for a humoral-mediated allo-response, not only by the pioneers in this field but also by many other centres which have included the use of C4d immunostaining during the work-up of allograft dysfunction [4,6].

In the present study, all biopsies performed due to graft dysfunction during a defined observation period were selected and C4d immunostaining was performed, irrespective of histological diagnosis. The overall C4d positivity was 45% (57 of 126) in this study which is compatible with other studies having C4d positivity varying from 22 to 62% [11,12]. In the present study, 40% of the biopsies (51 of 126) demonstrating the features of acute rejection comprised P-AbAR (n = 17, 12.7%), P-AbA + ACR (n = 12, 9%), ACR (n = 10, 7.5%) and P-AbAR + BK N (n = 1). The actual percentage of acute rejection in the different studies varies markedly between 10 and 60% due to selection of patients, time since graft and clinical indication of biopsies [8,13,14]. In the present study, the overall C4d positivity in acute rejection was 54.9%. Its break-up in individual groups of acute rejection was as follows: 80% in P-AbAR, 58% in ACR + P-AbAR and 20% in ACR. C4d positivity was scanty in pure acute cellular rejection compared to P-AbAR. Similar observations have been made by other studies [9,12,15,16]. Herman et al. [17] studied the deposition of C4d in paediatric renal allograft biopsies and analysed morphological criteria of humoral rejection described by Banff (2003) and showed an overall C4d positivity to be 52%.

Analysis of C4d immunostaining with various histological changes of renal allograft biopsies correlates well with presumptive diagnosis of antibody-mediated rejection. In the present study, distinguishing morphological features of the C4d-positive rejection versus C4d-negative rejection included capillary margination by polymorphs in PTC (47% versus 3%), dilatation of PTC (61% versus 17%), acute tubular necrosis (28% versus 15%) and neutrophilic glomerulitis (12% versus 3%). No significant differences in C4d-positive rejection versus C4d-negative rejection were noted for interstitial inflammation (68% versus 65%), tubulitis (37% versus 65%) and severe vasculitis (4% versus 1.5%). However, statistically significant associations of C4d positivity were seen only with capillary margination of neutrophils in the PTC and dilatation of PTC with C4d-positive rejection (P value < 0.05). Mauiyyedi et al. [12] also noted more neutrophils in PTC (65% versus 9%), neutrophilic glomerulitis (55% versus 4%), neutrophilic tubulitis (55% versus 9%), severe necrosis in glomeruli (20% versus 0%) or arteries (25% versus 0%) in C4d-positive rejection. Nickeleit et al. [16] reported 57% glomerulitis and 45% end-arteritis in C4d-positive biopsies. In the study of Herman et al. [17], C4d positivity in PTC was associated with accumulation of polymorphonuclear cells in PTC.

Prior to the present study, Tipkov et al. [18] reported several specific morphological features in rejecting allografts that correlated with the presence of anti-class I antibody (AbAR) in the recipient. The biopsies from AbAR+ patients had a higher incidence of severe vasculitis and glomerulitis. Fibrin thrombi in the glomeruli and vessels, fibrinoid necrosis and dilatation of PTCs were also more frequent in the AbAR+ group. The biopsy specimens more often had polymorphonuclear leukocytes and monocytes/macrophage in the PTCs and glomeruli. In contrast, specimens of AbAR– patients showed tubulitis more often than the specimens of AbAR+ patients; moderate and severe tubulitis was present in 95% AbAR– patients versus 50% in AbAR+ patients (P = 0.002) Graft loss was higher in AbAR+ patients. Association of PTC dilatation was found with antibody-mediated rejection, but they did not use C4d immunostaining. Shimizu et al. [19] and Ozelemir et al. [20], in their experimental studies, also showed that antibody-mediated rejection involves the micro-vasculature of the graft kidney and is associated with dilatation and distortion along with destruction of PTC.

Overall C4d positivity in biopsies showing features of CAN was 38.8%. Transplant glomerulopathy showed a significant association with C4d positivity (P value = 0.05). No associations of C4d were found with any other features of CAN, although transplant arteriopathy is found more frequently in the C4d-positive group. Mauiyyedi et al. [21], in their pioneer study of C4d immunostaining in chronic allograft dysfunction, showed that 23 of 38 (61%) biopsies with features of chronic allograft rejection were C4d positive and correlated well with antidonor HLA antibodies. Herman et al. [18] showed that 10 of 20 biopsies (50%) with features of chronic allograft nephropathy were C4d positive, and there was significant association of transplant glomerulopathy with C4d positivity.

C4d immunostaining was negative in all cases of acute pyelonephritis, acute cortical necrosis, membrano-proliferative glomerulonephritis, focal segmental glomerulosclerosis and CAN with BK nephropathy. Nonspecific weak positivity of the atrophic tubular basement membrane (TBM) was seen; however, the rest of the area TBMs were negative. Collins et al. [8] made similar observations. In contrast to Collins [8] and Andrew [9], we did not find C4d positivity in the vessels with fibrin thrombi and arterioles and arterial intima.

C4d-positive cases had a higher mean value of serum creatinine at the time of biopsies. But no correlation of C4d positivity and serum creatinine at the time of maximum follow-up was found. In the present study, no correlation of C4d immunostaining with donor serum antibodies (DSA) was performed. However, previous studies clearly show a high specificity (96%) and sensitivity (93%) between C4d and DSA [9,12,15]. This is the first Indian prospective study to document C4d immunostaining in acute rejection as well as chronic allograft nephropathy.

Individual histological features like capillary margination of polymorphs and dilatation of peritubular capillaries (PTC-D), glomerulitis, fibrin thrombi, acute tubular necrosis and fibrinoid necrosis were more common in the C4d positive group. These morphological features are helpful to differentiate acute antibody-mediated rejection from acute cellular rejection.

In the present study, no correlation of C4d immunostaining with DSA was performed. This remains the main drawback of this study. However, previously mentioned studies clearly show a high specificity (96%) and sensitivity (93%) between C4d and DSA [8,9,15].

In the end, it can be stated that C4d immunostaining is a useful marker, not only in the diagnosis of acute antibody-mediated rejection episodes, but also in biopsies with CAN that fail to correlate the degree of graft dysfunction with morphological features. It appears that the humoral limb of rejection has a role not only in the early post-transplant period, but also in late cases of chronic allograft nephropathy. C4d immunostaining deserves a place in the biopsy diagnosis of graft dysfunction.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Discussion
 References
 

  1. Solez K, Axelsen RA, Benediktsson H, et al. International standardization of criteria for the histologic diagnosis of renal allograft rejection. The Banff working classification of kidney transplant pathology. Kidney Int (1993) 44:411–422.[Web of Science][Medline]
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  8. Collins AB, Schneeberger EE, Pascual MA, et al. Complement activation, in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in peritubular capillaries. J Am Soc Nephrol (1999) 10:2208–2214.[Abstract/Free Full Text]
  9. Herzenberg AM, Gill JS, Djurdjev O, et al. C4d deposition in acute rejection: an independent long-term prognostic factor. J Am Soc Nephrol (2002) 13:234–241.[Abstract/Free Full Text]
  10. Finkilstein FO, Siegel NJ, Bastl C, et al. Kidney transplant biopsies in the diagnosis and management of acute rejections. Kidney Int (1976) 10:171–176.[CrossRef][Web of Science][Medline]
  11. Feucht HE, Felber E, Gokel MJ, et al. Vascular deposition of complement—split products in kidney allografts with cell-mediated rejection. Clin Exp Immunol (1991) 86:464–470.[Web of Science][Medline]
  12. Mauiyyedi S, Crespo M, Collins AB, et al. Acute humoral rejection in kidney transplant: II. Morphology, immunopathology and pathologic classification. J Am Soc Nephrol (2002) 13:779–787.[Abstract/Free Full Text]
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  15. Nickeleit V, Zeiler M, Gudat F, et al. Detection of the complement degradation product C4d in renal allografts: diagnostic and therapeutic implications. J Am Soc Nephrol (2002) 13:242–251.[Abstract/Free Full Text]
  16. Regele H, Exner M, Watschinger B, et al. Endothelial C4d deposition is associated with inferior kidney allograft outcome independently of cellular rejection. Nephrol Dial Transplant (2001) 16:2058–2066.[Abstract/Free Full Text]
  17. Herman J, Lerut E, Van Damme-Lombaerts R, et al. Capillary deposition of complement C4d and C3d in pediatric renal allograft biopsies. Transplantation (2005) 79:1435–1440.[CrossRef][Web of Science][Medline]
  18. Tipkov K, Campbell P, Pazderka F, et al. Pathologic features of acute renal allograft rejection associated with donor-specific antibody. Analysis using the Banff grading scheme. Transplantation (1996) 61:1586–1592.[CrossRef][Web of Science][Medline]
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Received for publication: 4. 6.07
Accepted in revised form: 29.10.07


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