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Keywords:

  • Complement C4d;
  • graft rejection;
  • humoral alloreactivity

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Why Is Complement C4d a Unique Marker of Humoral Alloreactivity?
  5. Prevalence of Capillary C4d
  6. Immunohistology of Capillary C4d
  7. Histopathology and Capillary C4d
  8. Etiology of Capillary C4d
  9. Discrepancies Between Serology and Immunohistology of Humoral Alloreactivity
  10. Clinical Relevance of Capillary C4d
  11. Therapeutic Options
  12. References

Staining of C4d in graft capillaries has emerged as a useful method to detect antibody-mediated rejections in situ. Demonstration of capillary C4d has provided substantial clinical results and allows several conclusions: Antidonor antibodies (preformed or produced de novo) activate complement directly in the graft. Capillary C4d is present in about 30% of biopsies with acute and chronic rejections and separates rejections with a humoral component from ‘pure’ cell-mediated rejections. Recognition of humoral alloreactivity is important, since effective treatment is now available. Since capillary C4d can appear and disappear at any time post transplantation, every transplant biopsy should be tested. Capillary C4d is now incorporated in the ‘Banff classification’. The incidence of C4d-positive cases will probably decline because of the ‘routine’ application of potent immunosuppressants, including mycophenolate mofetil, that can inhibit antibody production. Presensitization, however, will remain a potential threat to allografts.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Why Is Complement C4d a Unique Marker of Humoral Alloreactivity?
  5. Prevalence of Capillary C4d
  6. Immunohistology of Capillary C4d
  7. Histopathology and Capillary C4d
  8. Etiology of Capillary C4d
  9. Discrepancies Between Serology and Immunohistology of Humoral Alloreactivity
  10. Clinical Relevance of Capillary C4d
  11. Therapeutic Options
  12. References

The immune system can use cellular and humoral effector mechanisms in order to combat invading pathogens. In the case of solid organ transplantation, histological studies during rejection regularly showed lymphocytes infiltrating the graft, but no humoral effector molecules (with the exception of hyperacute rejection). Transplant rejection was therefore believed to be cell mediated, whereas humoral immunity was thought to play no role. In kidney transplantation the ‘Banff classification’ (1) was eventually formulated, representing a comprehensive analysis of cell-mediated alloreactivity.

However, two clinical settings: (i) humoral presensitization of recipients and (ii) de novo sensitization after transplantation, were not satisfactorily explained by cellular immunity. It was puzzling that recipients with a high percentage of ‘panel-reactive antibodies’ before transplantation had lower graft survival rates despite a negative cross-match test [reviewed in (2)]. Graft survival rates were also markedly lower when donor-specific antibodies appeared de novo after transplantation. Rejections were more severe, often accompanied by endothelial injury and vasculitis, and resistant to conventional antirejection therapy (3, 4, reviewed in 5). Also experimental studies suggested the contribution of alloantibodies to vascular injury in acute and chronic allograft rejections (6,7). Because of the negative histological results, the precise pathogenetic role of alloantibodies remained undefined. The question was whether the presence of alloantibodies simply indicated an enhanced immunological reactivity of the recipient, or whether antibodies could act directly in a graft.

This question can now be answered, because the missing link in the recognition (and manifestation) of humoral alloreactivity has been detected. Ten years after its first description (8), capillary deposition of complement C4d in graft biopsies is widely recognized as a unique immunohistological marker of antibody-mediated alloreactions.

Why Is Complement C4d a Unique Marker of Humoral Alloreactivity?

  1. Top of page
  2. Abstract
  3. Introduction
  4. Why Is Complement C4d a Unique Marker of Humoral Alloreactivity?
  5. Prevalence of Capillary C4d
  6. Immunohistology of Capillary C4d
  7. Histopathology and Capillary C4d
  8. Etiology of Capillary C4d
  9. Discrepancies Between Serology and Immunohistology of Humoral Alloreactivity
  10. Clinical Relevance of Capillary C4d
  11. Therapeutic Options
  12. References

Circulating alloantibodies encounter the grafted endothelium as the first target. Living endothelial cells can rapidly eliminate bound antibodies from the cell surface by ‘capping’, ‘shedding’ or ‘internalization’[reviewed in (9)]. The components of the classical complement cascade are also rapidly degraded by cell-bound and circulating control proteins (10), as the bloodstream permanently clears the endothelial surface. Conventional immunohistological techniques that detect Ig molecules or large complement proteins fail in this situation (in contrast to the situation when deposits of antibodies/immune complexes are retained on inert basement membranes, or in connective tissues that are not directly exposed to blood).

Among the variety of complement proteins, the opsonins C4 and C3 are privileged because they possess an internal, ‘protected’ thioester (11). This moiety enables complement C4 (and C3) to form covalent bonds with accessible target molecules upon activation, thereby generating the C4b (C3b) molecule. Because of the short-lived reactivity of the thioester, activation of the complement cascade is focused on nearby targets, but uncontrolled systemic activation is precluded. Following proteolytic cleavage of C4b, the split product C4d remains covalently bound to target structures, whereas larger fragments such as C4c (C3c and probably also the terminal complex C5b-9), go into solution.

Complement C4d represents the alpha-2 portion (mol. wt. about 42 kDa) of complement C4. The major biological properties of complement C4 are assembled in this region. It contains the thioester which mediates covalent binding, carries the discriminating residues of the C4A and C4B isotypes and most of their polymorphic determinants, the Chido and Rodgers blood groups and also the binding sites for complement C3 and the complement receptor type I. There is no apparent biological function associated with C4d alone.

C4d is, however, the stable (target-bound) remnant of classical complement activation and can reveal humoral attacks against endothelial cells that escape detection by other methods. In the past, histological detection of C4d, and hence recognition of humoral alloreactivity, was obscured because the commonly used polyvalent anti-C4 reagents reacted with determinants of the C4c fragment, but not with the alpha-2 (C4d) portion of C4 (12), (Figure 1).

image

Figure 1. Deposition of complement C4d in interstitial and glomerular capillaries in a kidney graft with delayed function; absence of complement C4c(immunoperoxidase staining).

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Prevalence of Capillary C4d

  1. Top of page
  2. Abstract
  3. Introduction
  4. Why Is Complement C4d a Unique Marker of Humoral Alloreactivity?
  5. Prevalence of Capillary C4d
  6. Immunohistology of Capillary C4d
  7. Histopathology and Capillary C4d
  8. Etiology of Capillary C4d
  9. Discrepancies Between Serology and Immunohistology of Humoral Alloreactivity
  10. Clinical Relevance of Capillary C4d
  11. Therapeutic Options
  12. References

The prevalence of capillary C4d in renal graft biopsies depends on the clinical situation of the recipients. In the setting of ‘delayed graft function’, especially when presensitized recipients were involved (i.e. patients with preformed antibodies and regrafts), about 50% of biopsies showed either diffuse or focal staining of interstitial, peritubular capillaries (13). In grafts with acute rejection, 30% of biopsies were found to be positive (14,15). In grafts with a strict definition of chronic rejection, 60% of biopsies showed capillary C4d (16). The true prevalence of capillary C4d post transplantation is not yet known and awaits clarification by the assessment of protocol biopsies.

In heart transplants, C4d was present in about 40% of 33 patients (17) and in 50% of 155 endomyocardial biopsies from 56 patients (18).

It should be noted that the majority of these patients were recruited in the cyclosporine era, when humoral alloreactivity was relatively unopposed.

Immunohistology of Capillary C4d

  1. Top of page
  2. Abstract
  3. Introduction
  4. Why Is Complement C4d a Unique Marker of Humoral Alloreactivity?
  5. Prevalence of Capillary C4d
  6. Immunohistology of Capillary C4d
  7. Histopathology and Capillary C4d
  8. Etiology of Capillary C4d
  9. Discrepancies Between Serology and Immunohistology of Humoral Alloreactivity
  10. Clinical Relevance of Capillary C4d
  11. Therapeutic Options
  12. References

In normal kidneys, C4d resides in every glomerular mesangium and in arterioles at the vascular pole, reflecting the continuous, physiological renal turnover of immune complexes. When immune complex-mediated renal disease develops, C4d also spreads into glomerular capillaries (12). Only transplanted kidneys in addition show deposition of C4d in interstitial, peritubular capillaries (8). If present, deposits of C4d can be detected in a given biopsy, either in every capillary (diffuse staining), or in few capillaries only (focal staining). It was shown early that the appearance of capillary C4d can follow a dynamic course (13). As such, the staining of few capillaries indicates a transitional state, either representing an ongoing humoral attack (resulting later in diffuse staining) or the ‘wash-out phase’ of a previous attack (15,19,20). Focal staining of C4d is therefore clinically relevant (13, 19), which contradicts other statements (21). When interstitial capillaries show C4d, glomerular capillaries are also positive (8). Discrepant results (i.e. weak or absent glomerular staining in the presence of positive interstitial capillaries) have been reported (20,22), but for technical reasons (see below). C4d is attached to endothelial cells and to basement membranes (20,22). In grafts with chronic dysfunction, staining of atrophic tubules is sometimes seen and is considered to be nonspecific (15), albeit linear deposition of C3 along tubular basement membranes was associated with markedly reduced graft survival in an early study (23).

The terminal complex C5b-9, when present, was found in glomerula and around tubules, but infrequently in interstitial capillaries (8,24). Whether classical complement activation in graft capillaries would proceed to the generation of the terminal complex has not been established so far, at least in renal transplantation. Data from clinical lung transplantations (25) are in favor of this pathogenetic pathway.

Technical considerations

Cryostat slides and monoclonal anti-C4d antibodies are generally used in immunoperoxidase staining or indirect immunofluorescence. A polyvalent C4d-reactive antiserum was introduced recently that also stains paraffin slides, thus obviating the need for cryopreserved tissue (26). There may be differences in the sensitivity of either method, especially with regard to the staining of glomerular and also interstitial capillaries. Mesangial C4d deposits (which should always be present) could serve as a positive internal control for staining, but glomerula may be absent in a given biopsy, or the technique applied (e.g. indirect immunofluorescence, or use of paraffin slides) may not detect such deposits. Regular testing of lymphoid tissue (e.g. slides from tonsils), where germinal centers should produce bright C4d staining (27), is therefore recommended in order to ensure the application of optimal reagents and techniques (personal experience).

Histopathology and Capillary C4d

  1. Top of page
  2. Abstract
  3. Introduction
  4. Why Is Complement C4d a Unique Marker of Humoral Alloreactivity?
  5. Prevalence of Capillary C4d
  6. Immunohistology of Capillary C4d
  7. Histopathology and Capillary C4d
  8. Etiology of Capillary C4d
  9. Discrepancies Between Serology and Immunohistology of Humoral Alloreactivity
  10. Clinical Relevance of Capillary C4d
  11. Therapeutic Options
  12. References

From the beginning, the immunohistology of capillary C4d did not match well with conventional histopathology. Striking discrepancies first appeared in grafts with delayed function. While pathologists sometimes noted ‘preservation injury’, ‘acute tubular necrosis’ or a combination of several findings, immunohistology already showed prominent capillary C4d staining (13). These original observations were later confirmed by studies that attributed capillary C4d also to ‘borderline lesions’ or even ‘0 grading’ according to the previous Banff classifications (19,26,28). Importantly, in such cases the presence of capillary C4d in the initial biopsies preceded the development of ‘vascular’ or humoral rejections that were later diagnosed by conventional pathology in repeat biopsies (13,14). It was likewise clear from the beginning that capillary C4d could separate ‘pure’ cell-mediated rejections from ‘mixed’ rejections (13).

The pathology departments in Harvard, Basel and Vienna have meanwhile provided detailed histopathological analyses of C4d-positive specimens.

Acute rejection (Table 1)

Table 1.  Association of capillary C4d with histological changes – classification and frequency of acute renal allograft rejection
Nickeleit et al. (15)Mauiyyedi et al. (21) 
Cap. C4d in 30% of biopsies:Cap. C4d in 29% of biopsies 
associated with:Proposed classification of acute rejection: 
Transplant glomerulitisAcute cellular rejection 
Tub. MHC II expressionType 1 (tubulointerstitial)48%
Interstitial cell. rejectionType 2 (endarteritis)22%
Transplant endarteritisAcute humoral rejection 
 Type 1 (capillary)22%
 Type 2 (art. fibrin. necrosis)7%

In the largest study to date, Nickeleit et al. (15) have investigated a total of 398 diagnostic biopsies performed in 265 patients because of deteriorating graft function. They found capillary C4d in 120 specimens (30%), predominantly in the early post-transplantation period, associated with signs of ‘active’ rejection (such as transplant glomerulitis, expression of HLA class II in tubules, interstitial cellular rejection and transplant endarteritis). In Harvard (22), the accumulation of neutrophils in C4d- positive capillaries was emphasized, confirming the earlier observations in antibody-associated rejections by Halloran's group (4). About 30% of all acute renal allograft rejections had a humoral component (14). On the basis of capillary C4d staining, the subdivision of acute rejections into acute cellular rejections (ACR) type I/type II and acute humoral rejections (AHR) type I/II was proposed. Thus it is clear that a simple description of ‘vascular rejection’, which does not distinguish between cell-mediated and antibody-mediated processes (as both can promote ‘vascular rejection’) is not sufficiently precise and might best be abandoned.

Chronic rejection

According to a strict definition of chronic renal allograft rejection in Harvard, 23 out of 38 cases (61%) showed capillary C4d (16). Conventional histopathology could not distinguish between C4d-positive and C4d-negative cases. In a large retrospective analysis, Regele et al. (20) detected capillary C4d in 73 out of 213 patients (34%) with chronic allograft dysfunction. It was associated with chronic transplant glomerulopathy/glomerulitis, multilayering of capillary basement membranes, tubular atrophy, and with accumulation of mononuclear cells in peritubular capillaries.

Taking these results together, it is obvious that conventional histopathology did not cover the entire spectrum of allograft rejection. In particular, the humoral component frequently escaped notice. Capillary C4d has therefore been added to the ‘Banff classification’ (29). Staining of C4d might also improve the diagnostic yield of ‘protocol biopsies’, which are performed at present in several centers in order to recognize and treat ‘subclinical rejections’ in time (30).

Etiology of Capillary C4d

  1. Top of page
  2. Abstract
  3. Introduction
  4. Why Is Complement C4d a Unique Marker of Humoral Alloreactivity?
  5. Prevalence of Capillary C4d
  6. Immunohistology of Capillary C4d
  7. Histopathology and Capillary C4d
  8. Etiology of Capillary C4d
  9. Discrepancies Between Serology and Immunohistology of Humoral Alloreactivity
  10. Clinical Relevance of Capillary C4d
  11. Therapeutic Options
  12. References

It is now well established that capillary C4d, representing an immunohistological imprint of classical complement activation, is induced by alloantibodies. The possibility of ‘ischemia-induced’ C4d, suggested in a study with cardiac transplants (17), has been ruled out formally using intraoperative kidney graft biopsies. Capillary C4d appeared as early as 1 h post transplantation and was associated with anti-donor antibodies (31). Thus, it should be considered whether, in heart transplantation also, it is not ‘ischemia’ which induces capillary C4d, but rather C4d-laden capillaries which promote ischemic injury. Capillary C4d is related neither to the administration of anti-lymphocyte preparations to recipients (13), nor to viral infections (15). Since capillary C4d is imported through the circulation, there is also no apparent role for complement factors produced within the kidney. Local synthesis of C3, a relevant factor in experimental renal transplantation (32), could, however, contribute to the deposition of complement around tubules (8,23,24).

Presensitization, including the presence of preformed alloantibodies, regrafts and previous pregnancies, emerged as the principal determinant for C4d positivity in the early post-transplantation period (8,28,33–36). Most antibodies are directed against HLA (see below). As human microvascular endothelial cells constitutively express both class I and class II (DR) antigens (in contrast to rodent endothelial cells, that carry only MHC class I determinants), class II-reactive antibodies also have to be considered. These are not detected in the conventional microcytotoxicity assay using panel cells, but require refined techniques (9). In 86 recipients with delayed graft function, 44 pretransplant serum samples showed reactivity with DR-typed lymphoblastoid cell lines by flow cytometry (21 against donor DR), opposed by 20 positive sera in the panel test. Capillary C4d was associated in corresponding biopsies post transplantation (33).

It was shown recently that sera from prospective recipients of first kidney grafts were harmful only if they contained class I- and class II-reactive alloantibodies together (37). Preformed antibodies against either class I or class II alone were not detrimental. Unfortunately, corresponding graft biopsies for the assessment of capillary C4d were not available in that study.

Capillary C4d was also associated with the de novo production of antidonor antibodies after transplantation. This can occur in the context of presensitization early after transplantation, and in the context of indirect allorecognition in longer-functioning grafts with chronic rejection (9). It will be interesting to determine whether the combined production of anti-class I and -class II antibodies exerts the strongest impact also in this situation.

In conclusion, capillary C4d in the early post-transplantation period is induced in part by preformed alloantibodies that escape conventional cross-match testing, and by antibodies that are rapidly produced de novo. De novo antibody production certainly accounts for the deposition of C4d in long-term grafts.

Discrepancies Between Serology and Immunohistology of Humoral Alloreactivity

  1. Top of page
  2. Abstract
  3. Introduction
  4. Why Is Complement C4d a Unique Marker of Humoral Alloreactivity?
  5. Prevalence of Capillary C4d
  6. Immunohistology of Capillary C4d
  7. Histopathology and Capillary C4d
  8. Etiology of Capillary C4d
  9. Discrepancies Between Serology and Immunohistology of Humoral Alloreactivity
  10. Clinical Relevance of Capillary C4d
  11. Therapeutic Options
  12. References

Several studies have put much effort into attempting to correlate capillary C4d with the concurrent presence of circulating alloantibodies. This correlation is, however, not perfect. The presence of C4d in the absence of circulating alloantibodies, and vice versa, has been found in a substantial number of cases (19,21,34).

It should be remembered, that peripheral lymphocytes or their derivatives usually serve as targets for the detection of HLA antibodies in vitro, whereas microvascular endothelial cells are the target of C4d in vivo. The differences in their antigenic profile deserve close attention (Table 2). In particular, from the class II determinants, only DR alleles are constitutively expressed on human capillary endothelial cells, but not DP and DQ alleles (38). Arterial endothelial cells do not even show DR determinants. On the other hand, endothelial cells exhibit antigens that are not expressed on lymphocytes.

Table 2.  Targets of alloantibodies
In vitro (CDC, flow cytometry, ELISA)In vivo (immunohistology C4d)
lymphocytes, soluble HLA moleculescapillary endothelial cells
  1. Compiled from: (38,39).

HLA class IA++ 
 B++ 
 C++ 
HLA class IIDR++(arteries –)
 DP+ 
 DQ+ 
Endothelial antigens + 
(ABO; X)

As such, the discrepant results with C4d vs. circulating antibodies could be readily explained by the antigenic diversity of lymphocytes and endothelial cells [ABO antibodies, for instance, precipitate C4d in graft capillaries (39) but escape testing of donor lymphocytes]. More importantly, the presence of capillary C4d in the absence of circulating alloantibodies can also result from ‘in vivo immunoadsorption’. Especially in presensitized recipients, all preformed antibodies might be trapped within the graft and de novo production of antibodies may not occur. Similarly, the titer of circulating antibodies may be well below the threshold of in vitro tests, but accumulation of antibodies within the graft (thereby increasing antibody concentration) is finally sufficient for complement activation and deposition of C4d in situ. That in vivo immunoadsorption in fact occurs has already been documented in early studies where antibodies reactive against capillary endothelial cells could be eluted from graft nephrectomies. In most cases, these antibodies were not detectable in the peripheral circulation while the graft was in place, but appeared after removal of the graft (40).

With regard to the second scenario (absence of C4d but presence of circulating antibodies), a study by Böhmig et al. (34), involving 113 diagnostic biopsies from 58 recipients, is informative. Among three groups of patients (I: C4d+/antibody+/–; II: C4d–/antibody+ III: C4d–/ antibody–), graft function at 1 year post biopsy was compromised only in group I (C4d +; serum creatinine 2.8 mg%), whereas groups II (C4d–/antibody+) and III (C4d–/antibody–) showed comparable function (serum creatinine 1.8 mg% and 1.6 mg%, respectively). These results do not necessarily indicate a low sensitivity of capillary C4d staining, as was suggested by the authors. An alternative explanation would be that, out of an array of measurable alloantibodies in vitro, only antibodies that are relevant in vivo generate capillary C4d. Consequently, antibodies directed against HLA DP or DQ determinants would not precipitate C4d in capillaries.

Given these discrepancies, and the variety of available techniques for antibody detection, the requirement of circulating antibodies (in addition to C4d) in order to establish a firm diagnosis of humoral rejection (21) is not warranted on clinical and practical grounds.

Clinical Relevance of Capillary C4d

  1. Top of page
  2. Abstract
  3. Introduction
  4. Why Is Complement C4d a Unique Marker of Humoral Alloreactivity?
  5. Prevalence of Capillary C4d
  6. Immunohistology of Capillary C4d
  7. Histopathology and Capillary C4d
  8. Etiology of Capillary C4d
  9. Discrepancies Between Serology and Immunohistology of Humoral Alloreactivity
  10. Clinical Relevance of Capillary C4d
  11. Therapeutic Options
  12. References

Renal grafts with capillary C4d have lower survival rates than grafts without C4d. The first clinical study (13) investigated 93 recipients with ‘delayed graft function’ and found the majority of early graft losses (21 out of 25) contained within the C4d-positive group. Other studies have confirmed the association of C4d with reduced graft survival (14,22,26,36). Consequently, capillary C4d is the strongest independent predictor of subsequent graft loss (19,36) and graft dysfunction (34). It is worth noting that capillary C4d had the strongest impact on graft survival when it was present in early biopsies [i.e. in biopsies taken within 6 months after transplantation (19)].

Controversies regarding the clinical relevance of capillary C4d have emerged primarily in studies on chronic graft dysfunction. In the study by Nickeleit et al. (15), C4d-positive and -negative grafts had comparable survival rates. Mauiyyedi et al. (16) even reported an improved survival of C4d-positive cases 1 year post biopsy. A ‘protective’ role of capillary C4d was finally suggested in a recent contribution by Platt (41).

As already mentioned, the effects of humoral alloreactivity seem to be much weaker in the late post-transplantation period (19), possibly as a consequence of maintenance immunosuppression. In the studies from Basel and Harvard (15,16), detection of C4d gave rise to intensified immunosuppressive therapy, resulting in improved clinical outcomes (see below). The proposed ‘protective’ role of capillary C4d is interesting from a theoretical point of view. Well-functioning, C4d-positive grafts can indeed be encountered, but these are the exception and not the rule. Whether capillary C4d in these instances indicates a state of ‘accommodation’[i.e. growing resistance of endothelial cells against humoral effectors (41)], or is related to the presence of ‘harmless’ antibodies (perhaps antibodies of a given isotype and low affinity), or to both conditions together, remains to be determined. The studies showing a reduced survival of C4d-positive grafts, and also the observation that capillary C4d precedes the development of chronic transplant glomerulopathy (20), are not compatible with a protective role of C4d. Finally, capillary C4d is a clinically relevant factor not only in kidney transplantation, but also in heart (17,18) and lung transplantation (25).

It should be remembered, however, that it is not clear whether graft dysfunction results from the transient binding of antibodies (42), or ultimately from complement activation inducing both endothelial damage and also endothelial activation (43).

Therapeutic Options

  1. Top of page
  2. Abstract
  3. Introduction
  4. Why Is Complement C4d a Unique Marker of Humoral Alloreactivity?
  5. Prevalence of Capillary C4d
  6. Immunohistology of Capillary C4d
  7. Histopathology and Capillary C4d
  8. Etiology of Capillary C4d
  9. Discrepancies Between Serology and Immunohistology of Humoral Alloreactivity
  10. Clinical Relevance of Capillary C4d
  11. Therapeutic Options
  12. References

Acute humoral rejection requires prompt application of specific, intensified immunosuppression in order to avoid impending graft loss. Following the arguments above, acute humoral rejection has to be assumed in all C4d-positive cases with delayed or deteriorating graft function in the early post-transplantation period, irrespective of conventional histopathology findings.

Removal of alloantibodies from the circulation is accomplished by plasmapheresis or immunoadsorption. These basic procedures have been variably supplemented with application of tacrolimus, mycophenolate mofetil (MMF), anti-thymocyte globulins or high-dose intravenous immunoglobulins (Table 3). Using immunoadsorption by protein A (28), good graft function could be restored in eight out of ten patients with acute humoral rejection (nine being on hemodialysis at the time of biopsy). Based on these encouraging results, a multicenter trial has been initiated in order to show whether immunoadsorption is more effective than standard antirejection therapy. In highly sensitized recipients (regrafts with panel-reactive antibodies greater than 50%) peri-operative immunoadsorption was performed successfully (44).

Table 3.  Treatment modalities in humoral rejection
Acute humoral rejection:
 Plasmapheresis (× 10) + Tacrolimus + Mycophenolate
 Crespo et al. (35)
 Immunoadsorption (× 9) ± anti-thymocyte globulin ± Mycophenolate
 Böhmig et al. (28)
 Plasmapheresis + IVIG
 Montgomery et al. (46)
Chronic rejection:
 Mycophenolate + Tacrolimus
 Theruvat et al. (45)

In patients with chronic graft dysfunction, de novo production of alloantibodies could be controlled by the combination of MMF plus Tacrolimus (45).

In the future, it will be important to establish safe treatment protocols with regard to the duration of intensified immunosuppression in such cases, as the long-term sequelae of over-suppression must also be avoided. Sequential assessment of capillary C4d, or perhaps also the excretion of soluble C4d in urine (24), could guide individual therapeutic regimens.

All the therapeutic interventions up to now have aimed at the removal of alloantibodies or the control of their production. It would certainly be interesting also to investigate the effects of complement inhibition.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Why Is Complement C4d a Unique Marker of Humoral Alloreactivity?
  5. Prevalence of Capillary C4d
  6. Immunohistology of Capillary C4d
  7. Histopathology and Capillary C4d
  8. Etiology of Capillary C4d
  9. Discrepancies Between Serology and Immunohistology of Humoral Alloreactivity
  10. Clinical Relevance of Capillary C4d
  11. Therapeutic Options
  12. References
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