Blog entry by Arif Khwaja

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by Arif Khwaja - Friday, 8 April 2016, 9:30 AM
Anyone in the world

Whilst the benefits of transplantation are well established, finding suitable donors for ‘sensitised’ patients with anti-HLA antibodies remains a significant barrier to transplantation. The options for such patients are to stay on the deceased donor waiting list, participate in the paired+pooled donation scheme (and hope they get a donor) or undergo densistisation and transplant from a live HLA incompatible (HLAi) donor. However the outcomes HLAi live donor transplantation are significantly worse than those receiving compatible kidneys. In reality given the chances of receiving an HLA compatible transplant are so slim, the choice these patients face is to either be desensitised and receive an HLAi live kidney or remain on dialysis.

In a recent publication in NEJM Orandi and colleagues from John Hopkins look at the real world outcomes for such patients in elegant observational analysis. They looked at the outcomes of 1025 kidney transplant recipients (from 22 centres) who received a kidney from an HLAi live donor. As there are significant differences in  the techniques used to measure HLA antibodies they looked ONLY at patients who underwent perioperative densistisation for donor-specific antibodies ( the treatment protocols were not analysed as there was centre to centre variation).
They then compared the outcomes to 2 sets of controls i) sensitised patients who were waitlisted and then subsequently received a deceased donor transplant and ii) waitlisted patients who didn’t receive a transplant. For each recipient there were 5 matched controls. patients.  Controls had similar levels of panel reactive antibody as well as other factors that are known to effect graft outcome including age, blood group, diabetes, RRT prior to transplant, previous transplants etc. The levels of HLA antibody were classified as i) low (positive luminex assay but negative flow-cytometric crossmatch) ii) moderate (positive flow-cytometric crossmatch but negative cytotoxic crossmatch (CDC) and iii) high (positive CDC).
At 8 years patients who had received an HLAi transplant from a live donor had a survival of 76.5% versus 62.9% for the waiting list/deceased-donor transplant group versus 43.9% for the waiting list only group (p<0.001). Interestingly  this benefit held across all levels of donor specific antibody ( i.e. no matter how strong the crossmatch). So those with low levels of anti HLA antibody (as defined above) who underwent HLAi live transplant had 89.2 survival at 8 years compared to 65% (in the waitlist/deceased-donor transplant group) and 47% (in the waitlist only group). Even in the high donor specific antibody group ( i.e those with a positive CDC)  survival at 8 years was 71% versus 61.5%(p=0.004) and 43.7% (p<0.001) in the control groups. A sensitivity analysis showed there was no ‘centre effect’ suggesting that outcomes were comparable even in centres that did relatively small numbers of HLAi transplants. The survival benefits of transplantation were seen from 1 month in the low donor specific antibody group (i.e. positive luminex but negative flow cytometric crossmatch). Unsurprisingly the benefits of live donor HLAi transplantation were seen at a later time point in the high donor specific antibody ( i.e. positive CDC)  group occurring at 4.8 months ( when compared to those who remained on the waiting list) and 21.7 months (when compared to those who remained on waiting list or received a deceased donor transplant).
So what does this tell us - i) dialysis is always a high risk option for patients with end stage kidney disease as outcomes are so much worse than transplantation - whether they are diabetic, obese, or at immunological risk. This needs to be borne in mind when making treatment decisions about listing and transplantation in such patients 
ii) the results of of the CDC positive group ( traditionally considered as an absolute barrier to transplantation) were surprisingly good though clearly there is significant ‘early’ graft loss will be a problem for patients and their clinicians
iii) clearly we need more information about what treatment protocols work best ( rituximab, plasma exchange , botezomib etc).
However what is clear is that HLAi live donor transplantation is deliverable, delivers significant survival advantage compared to patients staying on dialysis (which is what happens to most of such patients) and as the authors suggest can be done in clinical settings other than a single-centre, high volume, specialised centre.
[ Modified: Thursday, 1 January 1970, 1:00 AM ]