A new guideline on the management of highly sensitised kidney transplant patients—those who have high levels of human leukocyte antigens (HLAs) and are therefore more likely to experience allograft rejection—has been published by a European Society for Organ Transplantation (ESOT) working group.
Writing in Transplant International, Nizam Mamode (Guy’s Hospital, London, UK), Oriol Bestard (Vall d’Hebron University Hospital, Barcelona, Spain) and colleagues focus on a handful of key areas relating to the management of kidney transplant patients with HLA antibodies, from the definition of sensitisation, and place of kidney exchange programmes (KEPs) for sensitised patients, to desensitisation strategies and outcomes after HLA-incompatible transplantation.
“Although kidney transplantation rates have increased in many countries in recent years, highly sensitised patients typically spend longer waiting for a transplant, or may never receive one,” Mamode, Bestard and colleagues note. “This guideline is aimed at healthcare professionals who are faced with a patient with HLA antibodies, to provide advice regarding the most appropriate way to achieve a successful transplant.”
At the outset, the authors also state that this guideline does not include patients undergoing non-renal or multi-organ transplants, and does not consider paediatric recipients in detail.
Regarding the definition of sensitisation, the working group states that a parameter based on the HLA frequencies of the actual organ donor population—such as virtual panel reactive antibodies (vPRA) or calculated PRA (cPRA), or calculated reaction frequency (cRF)—should be used to estimate the chance that a sensitised patient can be transplanted with a compatible donor without the need for any special treatment.
They also highlight the fact that no European country has a published national consensus on its optimal recommended management pathway for highly sensitised patients, although several European centres have published protocols and outcomes following HLA-incompatible transplantation. As such, on the topic of organ allocation, they recommend an “active policy” of prioritising highly sensitised patients for organ transplantation using cPRA/cRF with a sliding-scale score.
Discussing the place of KEPs for highly sensitised patients, Mamode, Bestard and colleagues add that increased access to, and harmonisation of, KEPs with greater and standardised sharing of outcomes; inclusion of unspecified kidney donations (if these are performed); and inclusion of compatible pairs and deceased donor organs; should all be prioritised to increase the compatible donor pool.
“Entry into a KEP is the preferred initial option over desensitisation given the better transplant outcomes and cost-effectiveness—unless there is a need for desensitisation, clinical urgency, or a low chance of a transplant,” they continue. “The use of a KEP is preferred to desensitisation, but highly sensitised patients should not be left on a KEP list indefinitely if the option of a direct incompatible transplant exists, especially when there is a very low chance of finding a compatible organ.”
The working group’s main takeaway on desensitisation strategies is that “the most efficacious” approach is to start with rounds of plasma exchanges/immunoadsorption together with intravenous immunoglobulin (IVIG) or B-cell depletion using anti-CD20 monoclonal antibodies. They also note that newer therapies, such as imlifidase, may offer alternatives here, especially in the absence of living-donor transplantation.
Mamode, Bestard and colleagues do not highlight any specific recommendations regarding HLA-incompatible transplantation, citing the fact that “few studies compare HLA-incompatible transplantation with remaining on the waiting list, and comparisons of morbidity or quality of life do not exist”.
However, they do identify several other, wider strategies in managing highly sensitised kidney transplant patients, such as linking prioritisation policies across countries for equity of access, and the need for all KEPs to develop calculators to help assess the probability of an organ match. The working group concludes its recommendations by asserting the benefits of an integrated approach to these patients and that the aforementioned points “are not necessarily independent of each other”.
“Two points are worth emphasising—firstly, that for individual patients, the risks of the various options (including no transplant) should be assessed and conveyed using the limited data that are available,” they state. “Secondly, flexibility is important; a patient should not be left in a KSS [kidney sharing scheme] indefinitely if other options are available, or if new treatments appear.”
Future research areas
In its new guideline, the ESOT working group also outlines multiple areas in which further research is currently required, claiming that the further standardisation of single antigen bead assays (for detection and quantitation of HLA antibodies) and their interpretation is recommended. In addition, they state that better HLA matching on the basis of antibody epitopes—rather than antigens—and a restricted transfusion policy “will probably diminish the number of highly sensitised patients”, but more data are needed.
“As-yet-to-be-defined protocols, including proteasome inhibitors and other anti-plasmocyte antibodies with costimulation blockade, B-cell immunomodulation targeting IL-6 [interleukin 6], as well as cleavage of IgG [immunoglobin G] donor-specific antibodies [DSAs] with imlifidase, are highly promising new strategies that deserve further investigation,” Mamode, Bestard and colleagues continue.
“We recommend that data be collected prospectively for sensitised patients, in order to compare the effect of an HLA-incompatible transplant with remaining on the waiting list. These data should include mortality, morbidity and quality of life.”
Lastly, the authors support the continuation of work to develop schemes that may help patients with very high cPRA or cRF who may not be transplanted in kidney-paired donations or under deceased donor priority schemes, as well as further exploration into the role of induction immunosuppression in relation to sensitisation and its role in long-term outcomes, and determining whether better risk stratification, thorough immunological evaluation and avoidance of HLA-DSA can improve outcomes.