Biomedical subjects

Heinz Regele

Publications and source records attributed to Heinz Regele.

At least 37 records · Page 2Linked to original sources

PubMed2003

Diagnosis and treatment of antibody-mediated kidney allograft rejection.

Evidence of a significant pathogenetic role of donor-reactive antibodies (DRA) in kidney allograft rejection is accumulating. At least, partially owing to the recent discovery of the complement split product C4d as a valuable rejection marker, antibody-mediated rejection (AMR) has regained increasing attention. We review here the value of various diagnostic criteria, including immunohistochemistry (C4d staining), histomorphology and posttransplant serology, for the diagnosis of AMR. Furthermore, the mechanisms underlying alloantibody/complement-mediated allograft injury are discussed in detail. Finally, a thorough discussion of recently proposed "anti-humoral" therapeutic strategies is provided.

Acute Disease↗

PubMed2003

When renal allografts turn DARC.

BACKGROUND: The Duffy antigen-receptor for chemokines (DARC) is a chemokine-binding protein that is up-regulated on peritubular capillaries (PTC) during cellular renal allograft rejection. C4d deposition and accumulation of inflammatory cells in PTC are indicators of humoral renal allograft rejection. Because DARC is expressed at the site of C4d deposition and might be involved in inflammatory cell recruitment, the authors evaluated the expression of DARC in different forms of human renal allograft rejection. METHODS: Deposition of C4d and DARC expression were evaluated by immunohistochemistry in 42 renal transplant biopsy specimens. Biopsy specimens were subdivided according to histologic and immunohistochemical results, that is, C4d-negative biopsy specimens with (Banff 1, n=8) or without signs of cellular rejection (n=16), and C4d-positive biopsies (humoral rejection) with (Banff 1 rejection, n=7) or without cellular rejection (n=11). RESULTS: DARC expression was found on a small number of PTC and veins in patients without rejection. Cellular and humoral rejection led to a comparable increase in the number of DARC-positive PTC (9.7 and 8.7 vs. 2.6 vessels per high-power field [HPF], respectively). The highest numbers were found in biopsy specimens with signs of both humoral and cellular rejection (17.5 vessels per HPF). CONCLUSIONS: This is the first study that demonstrates an induction of a chemokine-binding protein at the site of C4d deposition in humoral allograft rejection. The additive effect of humoral and cellular rejection on DARC expression might imply different pathways of DARC induction for different forms of allograft rejection.

Acute Disease↗

PubMed2003

Flow cytometry based detection of HLA alloantibody mediated classical complement activation.

Complement-dependent cytotoxicity (CDC) panel reactive antibody (PRA) testing is used to assess recipient presensitization and post-transplant alloantibody formation in transplant recipients. However, CDC test results can be affected by false-positive reactions brought about by autoantibodies or antilymphocyte reagents. As an alternative to the CDC-PRA assay, detection of HLA alloantibodies using HLA antigen-coated microbeads (FlowPRA test) was recently established. FlowPRA testing, however, does not distinguish between (presumably more harmful) complement-fixing and noncomplement-fixing alloantibodies. In this study, we established a novel assay allowing flow cytometric detection of HLA alloantibody dependent classical complement activation using the FlowPRA test. For the detection of complement activation, FlowPRA beads were incubated with sera from highly sensitized dialysis patients (CDC-PRA reactivity >60%) and then stained for C4 (C4d, C4c) and C3 (C3d, C3c) fragments, as well as C1q deposition using indirect immunofluorescence. We demonstrate alloantibody induced induction of C4 fragment, and in parallel C1q deposition to HLA class I or class II beads. As shown by immunoblotting, C4 staining was not due to the presence of preformed C4 fragment-IgG/M complexes. Indeed, C4 fragment deposition in our in vitro system was demonstrated to result from de novo complement activation. First, inactivation of C4 by treatment of sera with methylamine, which inhibits cleavage of the internal thioester, completely abolished C4 fragment deposition. Second, C4 fragment deposition was not observed in the evaluation of C4-free immunoadsorption eluates obtained from highly sensitized dialysis patients. After supplementation with complement, however, eluates induced C4 deposition. Deposition of C4 split products and C1q was temperature-dependent with maximum binding after incubation at 4 degrees C for 60 min. In contrast, maximum C3 fragment deposition was found at 37 degrees C. At this temperature, C3 deposition occurred in an alloantibody and C4-independent fashion, presumably as a result of alternative complement activation. In summary, we describe a novel cell-independent and easy-to-perform PRA test that permits flow cytometry based detection of alloantibody induced classical complement activation. Future studies will have to evaluate its possible relevance as an alternative to CDC-PRA testing in clinical transplantation.

Case-Control Studies↗

PubMed2003

Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection.

Antibody-mediated rejection (AbAR) is increasingly recognized in the renal allograft population, and successful therapeutic regimens have been developed to prevent and treat AbAR, enabling excellent outcomes even in patients highly sensitized to the donor prior to transplant. It has become critical to develop standardized criteria for the pathological diagnosis of AbAR. This article presents international consensus criteria for and classification of AbAR developed based on discussions held at the Sixth Banff Conference on Allograft Pathology in 2001. This classification represents a working formulation, to be revisited as additional data accumulate in this important area of renal transplantation.

Graft Rejection↗

PubMed2003

Electroporation therapy in head and neck cancer.

OBJECTIVE: To prove the efficacy of electroporation therapy (EPT) in T1 and T2 squamous cell cancers of the oral cavity and oropharynx. MATERIAL AND METHODS: Twelve patients were treated with EPT within the framework of a European trial. Tumors were infiltrated with a bleomycin solution and subsequently treated with EPT. Four weeks after treatment the necrotic mass at the site of the former tumor was resected with save margins and accurately examined histologically. RESULTS: Whereas 10 specimens were completely free of cancer cells, 2 cases showed viable tumor cells. CONCLUSION: EPT has the potential to serve as an interesting alternative in the treatment of head and neck cancer.

Adult↗

PubMed2003

Glomerular immune deposits are associated with increased proteinuria in patients with ANCA-associated crescentic nephritis.

BACKGROUND: In small vessel vasculitis and its renal-limited form, idiopathic crescentic glomerulonephritis, renal damage is characterized by pauci-immune necrotizing crescentic glomerulonephritis (CGN) without histological evidence of immunoglobulin (Ig) deposition. In some patients, however, significant amounts of immune deposits may be detected. Therefore, we evaluated the clinical significance of these immune deposits in anti-neutrophil cytoplasmic autoantibody (ANCA)-associated pauci-immune CGN. METHODS: Renal biopsies of 45 consecutive patients with new onset of Wegener's granulomatosis, microscopic polyangiitis and idiopathic CGN were retrospectively evaluated by light microscopy, immunohistochemistry and electron microscopy and the findings compared with renal function and outcome. RESULTS: Typical pauci-immune CGN was found in 37 patients (group I). In eight patients (18%; group II), however, histopathological examination revealed substantial deposition of Ig in the mesangium and/or along the glomerular basement membrane. Five of these eight patients were cANCA positive; two initially had pANCA and developed a cANCA pattern and one was pANCA positive. There were no differences between groups in age, gender, renal function or extra-renal organ involvement at the time of biopsy. However, patients in group II had significantly more proteinuria (5.4+/-3.1 vs 1.3+/-1.0 g/24 h; P=0.016). We also observed a trend for a worse outcome with respect to renal function and mortality in group II patients; however, the differences did not reach significance. CONCLUSIONS: Our results confirm that in ANCA-associated CGN a substantial percentage of patients have evidence of Ig deposition in renal biopsies. In this subgroup, Ig deposition was associated with a significantly greater degree of proteinuria. Further investigations are necessary to define the full clinical impact of immune-complex deposition on the clinical course of renal disease in pauci-immune CGN.

Adult↗

PubMed2003

International variation in histologic grading is large, and persistent feedback does not improve reproducibility.

Histologic grading systems are used to guide diagnosis, therapy, and audit on an international basis. The reproducibility of grading systems is usually tested within small groups of pathologists who have previously worked or trained together. This may underestimate the international variation of scoring systems. We therefore evaluated the reproducibility of an established system, the Banff classification of renal allograft pathology, throughout Europe. We also sought to improve reproducibility by providing individual feedback after each of 14 small groups of cases. Kappa values for all features studied were lower than any previously published, confirming that international variation is greater than interobserver variation as previously assessed. A prolonged attempt to improve reproducibility, using numeric or graphical feedback, failed to produce any detectable improvement. We then asked participants to grade selected photographs, to eliminate variation induced by pathologists viewing different areas of the slide. This produced improved kappa values only for some features. Improvement was influenced by the nature of the grade definitions. Definitions based on "area affected" by a process were not improved. The results indicate the danger of basing decisions on grading systems that may be applied very differently in different institutions.

Europe↗

PubMed2003

Tissue injury and repair in allografts: novel perspectives.

PURPOSE OF REVIEW: Recent research achievements might considerably alter scientific concepts of pathways involved in tissue injury and repair. RECENT FINDINGS: Accumulating evidence for an important role of alloantibodies in acute and chronic allograft rejection led to a renewed interest in humoral kidney transplant rejection. Studies reassessing the mechanisms of antibody- and complement-mediated injury now shed new light on the pathogenic mechanisms underlying acute or chronic graft dysfunction and injury. A closer look at humoral effector mechanisms revealed that endothelial cell activation and injury may play a key role in humoral rejection, and further uncovered an important interplay between humoral and cellular alloimmunity. Regeneration of cells after injury has been thought to rely on activation of local progenitor cells. Recent investigation indicates that regeneration of grafted solid organs is not exclusively based on self-renewal of tissues but obviously also involves repopulation of the graft by recipient cells, creating chimerism in the vasculature and other compartments. Besides reparative compensation of cell loss, chimerism of endothelial cells might also alter immunologic properties of the graft, thus favoring adaptation and graft survival. On the other hand, however, myofibroblasts mediating deleterious arterial intimal proliferation may also be of recipient origin. A possible source of graft-repopulating recipient cells are bone marrow-derived adult stem cells with the amazing capacity of differentiating into cell types of all three germ cell layers. SUMMARY: Reliable diagnosis of humoral mechanisms in allograft rejection and identification of involved effector mechanisms should provide the basis for development and targeted application of specific anti-humoral treatment. Recently emerged new concepts of mechanisms underlying tissue regeneration might pave the way for entirely new therapeutic approaches in human disease.

Adaptation, Physiological↗

PubMed2002

A case of severe C4d-positive kidney allograft dysfunction in the absence of histomorphologic features of rejection.

Acute antibody-mediated (humoral) renal allograft rejection has emerged as a clinicopathological entity that carries a poor prognosis. Its diagnosis is based on typical pathohistologic features, serologic detection of donor-specific alloantibodies and the immunohistochemical finding of endothelial deposits of the complement split product C4d. We herein report a case of severe antibody-mediated graft injury after spousal-donor kidney transplantation. Despite an increased risk for humoral presensitization in the female recipient (three previous pregnancies), donor-specific alloantibodies were not detectable before transplantation. After initial graft function, severe graft dysfunction occurred one week after transplantation. A renal biopsy revealed no histomorphologic features of rejection. However, immunohistochemical detection of diffuse C4d deposits along peritubular capillaries suggested acute humoral rejection. The diagnosis of antibody-mediated rejection was confirmed by the detection of de-novo production of anti-donor alloantibodies. Graft dysfunction was resistant to high dose steroids or antilymphocyte antibody therapy. However, a recovery of graft function could be achieved by antibody elimination using immunoadsorption therapy. This case reinforces the high diagnostic value of C4d staining. In severe graft dysfunction humoral immune mechanisms should be considered, even when histopathologic features of humoral rejection are completely absent.

Adult↗

PubMed2002

A role for immune complexes in enhanced respiratory syncytial virus disease.

Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and viral pneumonia in infants and young children. Administration of a formalin inactivated vaccine against RSV to children in the 1960s resulted in increased morbidity and mortality in vaccine recipients who subsequently contracted RSV. This incident precluded development of subunit RSV vaccines for infants for over 30 years, because the mechanism of illness was never clarified. An RSV vaccine for infants is still not available. Here, we demonstrate that enhanced RSV disease is mediated by immune complexes and abrogated in complement component C3 and B cell-deficient mice but not in controls. Further, we show correlation with the enhanced disease observed in children by providing evidence of complement activation in postmortem lung sections from children with enhanced RSV disease.

Animals↗

PubMed2002

Derivation of nephrogenic adenomas from renal tubular cells in kidney-transplant recipients.

BACKGROUND: Nephrogenic adenomas are benign, tumor-like lesions within the urothelial mucosa of the urinary tract that are not uncommon in renal-transplant recipients. We investigated the origin of nephrogenic adenomas in renal-transplant recipients. METHODS: Tissue sections were analyzed by fluorescence in situ hybridization with the use of probes for the X and Y chromosomes, by immunohistochemical methods with the use of antibodies to renal tubular antigens, and by lectin histochemical methods. Forty-six nephrogenic adenomas from 29 patients were analyzed. RESULTS: All nephrogenic adenomas in 14 female recipients of transplants from male donors and 10 male recipients of transplants from female donors showed the same sex-chromosome status as the donor kidney, but not the same sex-chromosome status as the recipient's surrounding bladder tissue. The nephrogenic adenomas from all 6 female recipients of transplants from female donors showed female chromosomes, and those from the 16 male recipients of transplants from male donors showed male chromosomes. The presence of aquaporin 1, PAX2, and lectin-binding capacity for peanut agglutinin, Lotus tetragonolobus agglutinin, and Sophora japonica agglutinin in nephrogenic adenomas indicated an origin from renal tubular cells. CONCLUSIONS: Nephrogenic adenomas in renal-transplant recipients are derived from tubular cells of the renal transplants and are not metaplastic proliferations of the recipient's bladder urothelium.

Adenoma↗

PubMed2002

Treatment of systemic lupus erythematosus by immunoadsorption in a patient suffering from tuberculosis.

We report on a 40-year-old man, admitted with fever and weight loss, in whom systemic lupus erythematosus (lupus nephritis World Health Organization type IV) and concomitant acute lung tuberculosis were diagnosed. Conventional treatment of diffuse proliferative nephritis with cytotoxic drugs was thought to be too dangerous in the presence of active tuberculosis. A combination of immunoadsorption and steroids was instituted for the treatment of systemic lupus erythematosus. Antibodies against double-stranded DNA decreased, and proteinuria decreased from 10 g/24 hours to less than 1 g/24 hours. Tuberculosis was treated initially with quadruple-drug therapy, then a triple-drug protocol. Primarily enlarged lymph nodes decreased to normal size after 3 months. The combined treatment modality of steroids and immunoadsorption was effective and safe, even in this patient with active tuberculosis.

Administration, Oral↗

PubMed2002

Peri-operative immunoadsorption in sensitized renal transplant recipients.

BACKGROUND: Re-transplanted kidney allograft recipients with high levels of panel reactive antibodies (PRA) are at increased risk of early immunologic graft loss. In these patients, prophylactic peri-operative antibody depletion by immunoadsorption (IA) could prevent humoral graft injury and thus, in combination with anti-cellular rejection therapy, improve graft survival. METHODS: Twenty re-transplanted and broadly immunized cadaver kidney recipients (median PRA reactivity 87%, range 55-100%) were treated with IA (protein A) immediately before transplantation and during the early post-transplantation period (median number of IA sessions 11, range 1-24). Patients received additional prophylactic anti-lymphocyte antibody therapy. Nineteen patients had a negative pre-transplant cross-match. In one patient, a positive cross-match was rendered negative by the pre-transplant IA session. RESULTS: One-year graft survival was 80% and patient survival 95%. Median (range) serum creatinine in functioning grafts was 1.6 (0.8-2.7) mg/dl at discharge and 1.5 (1.0-5.8) mg/dl at 1 year. Two grafts were lost due to acute vascular rejection, whereby one rejection occurred after withdrawal of immunosuppression due to septicaemia. One patient had acute cellular rejection, which was reversed by a second course of anti-lymphocyte antibody therapy. Thrombotic microangiopathy and surgical complications were the causes for one graft loss each. Retrospective immunohistochemistry revealed peritubular C4d staining, a presumed marker for humoral alloreactivity, in 12 out of 15 biopsies. CONCLUSIONS: These results suggest that prophylactic peri-operative IA and anti-lymphocyte antibody therapy might be an effective therapeutic strategy for the prevention of early graft failure in sensitized re-transplant recipients.

Adult↗

PubMed2002

Acute humoral renal allograft rejection.

In kidney transplantation, it is well established that donor-specific antibodies can cause substantial graft injury. Hyperacute rejection, now virtually eliminated by routine pretransplant cytotoxic crossmatch testing, represents the prototype of humoral rejection. However, there is now increasing evidence that alloantibody-mediated immune reactions may also cause acute rejection. Acute humoral rejection, which is frequently associated with severe graft dysfunction and immunologic graft loss, represents a particular diagnostic and therapeutic challenge. Reliable detection of antibody-mediated graft injury is required to govern the application of antihumoral therapeutic strategies. This review focuses on new approaches in the diagnosis and treatment of acute humoral rejection. Special attention is given to a novel diagnostic marker, the complement split product C4d.

Antibody Formation↗

PubMed2002

Capillary deposition of complement split product C4d in renal allografts is associated with basement membrane injury in peritubular and glomerular capillaries: a contribution of humoral immunity to chronic allograft rejection.

Endothelial deposition of the complement split product C4d is an established marker of antibody-mediated acute renal allograft rejection. A contribution of alloantibody-dependent immune reactions to chronic rejection is under discussion. In this study, the association of immunohistochemically detected endothelial C4d deposition in peritubular capillaries (PTC) with morphologic features of chronic renal allograft injury was investigated in a large study cohort. C4d deposits in PTC were detected in 73 (34%) of 213 late allograft biopsies performed in 213 patients more than 12 mo after transplantation (median, 4.9 yr) because of chronic allograft dysfunction. Endothelial C4d deposition was found to be associated with chronic transplant glomerulopathy (CG) (P < 0.0001), with basement membrane multilayering in PTC (P = 0.01), and with an accumulation of mononuclear inflammatory cells in PTC (P < 0,001). Furthermore, C4d deposits in PTC (in biopsies with normal glomerular morphology) were associated with development of CG in follow-up biopsies. Other morphologic features of chronic allograft nephropathy (with exception of tubular atrophy) were not associated with C4d deposits in PTC. Analyses of previous and follow-up biopsies revealed that C4d deposits may occur de novo and may also disappear at any time after transplantation. In conclusion, the data suggest that complement activation in renal microvasculature, indicating humoral alloreactivity, contributes to chronic rejection characterized by chronic transplant glomerulopathy and basement membrane multilayering in PTC.

Adult↗

PubMed2002

Failure of BCL-2 up-regulation in proximal tubular epithelial cells of donor kidney biopsy specimens is associated with apoptosis and delayed graft function.

SUMMARY: In renal transplantation, postischemic acute renal failure (ARF) develops in more than 20% of patients. We investigated whether tubular epithelial cells obtained from donor kidneys without subsequent ARF express a different pattern of survival genes, compared with cells from kidneys exhibiting ARF. Donor kidney biopsy specimens were obtained before transplantation from eight recipients of cadaveric kidneys with primary graft function (CAD-PF), eight patients with biopsy-proven ARF without rejection (CAD-ARF), and eight recipients of living donor kidneys with primary graft function (LIV). One thousand proximal tubular epithelial cells per biopsy specimen were isolated by laser capture microdissection. Quantitative analysis of apoptosis and the apoptosis regulatory genes Bcl-2, Bcl-xL, and Bax were performed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling staining and real-time PCR, respectively. Primary cultures of human proximal tubular epithelial cells served as calibrator. The number of apoptotic cells was significantly higher in CAD-ARF compared with LIV and CAD-PF (1.5 +/- 1.1% [p < 0.05] vs. 0.3 +/- 0.2% vs. 0.4 +/- 0.2%; mean +/- SD). The apoptosis inhibitors Bcl-2 and Bcl-xL were significantly up-regulated in renal tubular cells of recipients without ARF compared with CAD-ARF. The ratios of Bcl-2/GAPDH normalized to calibrator were as follows: LIV 48 +/- 30, CAD-PF 38 +/- 55, and CAD-ARF 5 +/- 7 (p < 0.05). The corresponding ratios for Bcl-xL were as follows: LIV 6 +/- 6, CAD-PF 5 +/- 3, and CAD-ARF 1 +/- 1 (p < 0.05). No difference in the expression of the proapoptotic Bax could be observed. These data suggest that failure of proximal tubular cells to respond to injury by up-regulation of survival factors from the Bcl-2 family contributes to postischemic ARF in patients after cadaveric renal transplantation.

Apoptosis↗

PubMed2002

Ischemic conditioning prevents Na,K-ATPase dissociation from the cytoskeletal cellular fraction after repeat renal ischemia in rats.

Recent studies have suggested that heat shock proteins (HSPs) are involved in the restoration of the cytoskeletal anchorage of Na,K-ATPase after renal ischemia. To determine their role in ischemic conditioning, we investigated whether cytoskeletal Na,K-ATPase was stabilized during repeat ischemia concurrent with 25-kD and 70-kD HSPs induction. Anesthetized rats either underwent single unilateral renal ischemia or were conditioned with bilateral renal ischemia and, after 18 h of reflow, were then subjected to repeat unilateral renal ischemia. Renal cortex was harvested, and effects of single versus repeat ischemia were compared by Triton X-100 extraction, by immunohistochemistry, and by an in vitro assay of Na,K-ATPase association with isolated cytoskeletal fractions. In contrast to single ischemia, repeat ischemia did not result in increased Triton X-100 extractability of Na,K-ATPase. Levels of 25-kD and 70-kD HSPs were significantly induced by ischemic conditioning and redistributed into the cytoskeletal fraction after single and repeat ischemia. Immunohistochemistry also showed significant disruption of Na,K-ATPase within proximal tubules only after a single episode of ischemia, whereas repeat ischemia did not alter the pattern of restored Na,K-ATPase localization in conditioned renal cortex. The preserved association of Na,K-ATPase with the cytoskeletal fraction of conditioned renal cortex was effectively abolished in vitro by addition of antibodies against 25-kD or 70-kD HSP. These results suggest that 25-kD and 70-kD HSPs induced by ischemic conditioning stabilize the cytoskeletal anchorage of Na,K-ATPase during repeat renal ischemia.

Animals↗

PubMed2002

Capillary C4d deposition in kidney allografts: a specific marker of alloantibody-dependent graft injury.

Capillary deposition of the complement split product C4d has been discussed as a marker for antibody-mediated kidney allograft rejection. The relationship between C4d staining and posttransplant alloantibody detection remains to be thoroughly investigated, however. In this study, C4d staining in peritubular capillaries (PTC) and the incidence of alloantibody formation, as detected with sensitive techniques, were evaluated among a cohort of transplant recipients who had undergone biopsies and had not been selected for a specific histologic diagnosis. One hundred thirteen biopsies, obtained from 58 cadaveric kidney transplant recipients, were tested. Serum samples obtained at the time of biopsy were evaluated by flow cytometric crossmatch (FCXM) testing and FlowPRA (One Lambda, Inc., Canoga Park, CA) analysis of anti-HLA panel reactivity. Most biopsies with C4d deposits in PTC (C4d(PTC)(+), n = 21 of 24) were associated with positive posttransplant FCXM results (T and/or B cell FCXM) and/or > or =5% FlowPRA (anti-HLA class I and/or II) reactivity. Approximately 50% of the C4d(PTC)(-) biopsies were observed to be associated with donor-specific alloantibodies. Accordingly, high specificity (93%) but low sensitivity (31%) were calculated for capillary C4d staining (with FCXM testing as the standard method). For clinical evaluation, three patient groups were defined, i.e., a group of recipients with positive C4d staining in at least one allograft biopsy (C4d(PTC)(+), n = 16) and two C4d(PTC)(-) groups, which were discriminated on the basis of posttransplant FCXM results as C4d(PTC)(-)/FCXM(+) (n = 22) and C4d(PTC)(-)/FCXM(-) (n = 20) groups. Univariate analyses revealed significant differences between these groups with respect to serum creatinine levels at 12 mo [median, 2.83 mg/dl (interquartile range, 1.93 to 4.2 mg/dl) versus 1.78 mg/dl (1.47 to 2.24 mg/dl) versus 1.59 mg/dl (1.2 to 1.71 mg/dl), P < 0.001]. Of the five immunologic graft losses, four occurred in the C4d(PTC)(+) group and one occurred in the C4d(PTC)(-)/FCXM(+) group. In a multivariate analysis, C4d positivity was observed to have an independent predictive value for inferior 12-mo graft function (P = 0.02), whereas the observed moderate difference between C4d(PTC)(-)/FCXM(+) and C4d(PTC)(-)/FCXM(-) recipients did not achieve significance. In conclusion, these data demonstrate that positive C4d staining, which is an independent predictor of kidney graft dysfunction, represents a reliable specific marker for antibody-dependent graft injury.

Adult↗