POST TRANSPLANT PRODUCTION OF DONOR HLA SPECIFIC ANTIBODIES -CORRELATION WITH TRANSPLANT FAILURE AND GRAFT HISTOLOGY

 

J.E. Worthington1, S. Martin1, and L.J.McWilliam2

 

1.Transplantation Laboratory, Manchester Royal Infirmary, Manchester, United Kingdom. 2.Department of Histopathology, Manchester Royal Infirmary, Manchester, United Kingdom.

 

Introduction:

Recent data 1 have demonstrated a significant association between the production of donor HLA specific antibodies (HLA-Abs) and subsequent graft failure. This study aimed to correlate the presence of HLA-Abs in serum samples with graft biopsy data to address whether there is a distinct pathology as described by other groups 2 and to compare the biopsy findings in antibody positive (Ab+ve) and antibody negative (Ab-ve) cases.

 

Materials and Methods:

The study group comprised 115 adult recipients of primary renal transplants whose graft had failed. These cases had been transplanted between 1986 and 1998 and had been treated with cyclosporin based immunosuppression. The mean time to failure was 5.8 years (Range O -15.96 years). Sera taken pre-transplant and at 1,3,6 months and annually post- transplant were tested by enzyme-linked immunoabsorbent assay (ELISA) for the presence of class I and class II HLA-Abs. Antibody specificity was defined by a combination of cytotoxicity, ELISA and flow cytometry techniques to determine whether the antibodies were directed against donor mismatches. Graft biopsies were only performed for graft dysfunction and biopsy data was available for 54 of these recipients. The time to biopsy varied from weeks to several years with most biopsies taken at over 2 years post transplant.

 

Results:

All recipients were negative for donor specific HLA-Abs pre-transplant. Post-transplant, 58 of the 115 recipients produced donor specific HLA-Abs and their production was strongly predictive of transplant failure1. Biopsy data from 32 Ab+ve cases and 22 Ab-ve cases was available and the results are summarised in the table below. In the Ab-ve group 77% of cases showed chronic changes of chronic allograft nephropathy (CAN) compared to 55% in the Ab+ve group and 18% of Ab-ve cases showed either acute tubulointerstitial (Type I rejection) or vascular (Type II rejection) rejection compared to 44% in the Ab+ve group.  28% of cases in the Ab+ve group showed acute vascular rejection compared to 9% in the Ab-ve group. In only one case did the histology report describe features classically seen in antibody mediated rejection3.

 

 

Histology

Ab+ve n=32     

Ab-ve n=22

Chronic Allograft Nephropathy (CANa)

7

6

Chronic Allograft Nephropathy with features suggestive of chronic vascular rejection (CANb)

11

11

Acute Tubulointerstitial Rejection

(Type I rejection Banff 97)

5

2

Acute Vascular Rejection

(Type II and III rejection Banff 97)

9

2

Other

0

1

 

Conclusions:

Development of post transplant donor specific HLA-Abs is strongly predictive of transplant failure1.  We observed no clear cut biopsy “chronic” pathology reflecting this but there was a greater number of acute vascular rejection episodes in the Ab+ve group compared to the Ab-ve group as might be expected from previously published literature.  Immunostaining for C4d4 in these cases would be useful to see if it predicts antibody related chronic transplant failure.

 

References:

1 Worthington JE, Martin S, Al-Husseini DM, Dyer PA and Johnson RWG Transplantation 2003, 75 in press

2 Halloran PF, Wadgymar A, Ritchie S et al.  Transplantation 1990, 49:85-91

3 Trpkov K, Campbell P, Pazderka F et al.  Transplantation 1996 Jun 15;61 (II):1586-92

4 Regele H, Böhmig GA et al, J Am Soc Nephrol 2002 13:2371-2380