No such thing as a perfect match

No such thing as a perfect match
This post was prompted after reading a social media post stating that matching for kidney transplants was no longer necessary. That of course is not true, but it may have been the hope of transplant doctors as immunosuppressive drugs were developing apace during the latter part of the 20th century. I suspect the heading of a 2016 Medscape article: “Good match not always needed for living donor kidney transplant” could be the source of the confusion. That article was essentially saying that compared to staying on the waiting list, supported by dialysis, then even an unmatched kidney provided better survival statistics. 
So what does go into the matching process? Does it depend on where you live? What does it mean to have a mismatched transplant? 



Some explanations
ANTIGEN = a substance that is recognised as foreign to your body and can trigger an immune response which is aimed at defending the body
ANTIBODY = a protein made in B cells that attaches to the antigen and so labels it as “for destruction”. Some antibodies will directly neutralise the antigen while others just tag them for other cells to deal with. 
HLA = Human Leukocyte Antigens = a group of molecules that sit on the membrane of a cell acting as an ID label. They are unique to you and so can be used by the immune system to identify “self” from “non-self”. They are also referred to by the name “Major Histocompatibility Complex” or MHC. 
LEUKOCYTES = white cells 
LYMPHOCYTE = type of white cell. This can be

 B-CELLS = white cells that produce antibodies

 T-CELLS = white cells involved in the immune response; 3 main groups are 

  HELPER T-CELLS which trigger immune response

  KILLER T-CELLS which attack and kill the foreign material

  REGULATOR T-CELLS which suppress the immune response

———————————————————————————————————————————–

Matching for a kidney transplant


For kidney transplants the first element to be matched will be the blood group. From your point of view, as the recipient, the simplest blood type to be would be AB because this would allow you to receive an organ from a patient with any other blood group. Blood group O, however, means you can only have an organ from another person with blood group O. The rhesus antibodies that are commonly also mentioned alongside ABO grouping – the positive/negative – are not important when it relates to kidney transplants. 
The next matching test is also called ‘tissue typing‘ and this is where those HLA markers come into play. 
While the ABO system is a way of labelling red blood cells, the HLA system labels the white blood cells, which are the fundamental cells of the immune system. This system was described in 1952. The 1980 Nobel Prize in Physiology or Medicine was awarded to Jean Dausset, Baruj Benacerraf and George Snell for their discoveries and work with HLA. Snell introduced the concept of “H antigens”, Dausset demonstrated their existence and Benacerraf showed that the immune response was controlled by genetic factors. 

All cells have identification molecules on their surface, like a fingerprint. The immune system has to distinguish foreign antigens from those belonging to the body. For this they use the HLA molecules. They are called ‘human’ for obvious reasons – mice and other animals do have similar ones called MHC antigens. They are ‘antigens’ because they can provoke an immune response in another person, and the term ‘leukocyte’ means white cell and they were first discovered on human white blood cells.  

Broadly speaking HLA sit on the surface of cells, waiting to be recognised by other cells.  Imagine driving along a road looking at car number plates – you know which are local to your country and which are foreign visitors by the specific arrangement of letters and numbers. 
Class I and Class II

HLA are grouped into “class I”, which are the ones usually carrying the label “self” and occur on every cell with a nucleus, and “class II”, which are found on the so-called ‘professional antigen-presenting cells’ (APC) and lymphocytes. 

Class I HLA will effectively wave a piece of your own protein, a recognisable sign along the lines of “Hi, I belong to you, Have a nice day!”

Class II HLA will be displaying foreign proteins, shouting “Look what I found, you might want to take a closer look. This spells trouble!”

 APC  are akin to an army of guards trained to notice non-conformity – they ingest the abnormal foreign proteins, chomp them down into fragments (peptides) and then stick these fragments onto the HLA arms that protrude from the cell so other T cells can come along and eliminate them. 
Humans have 3 Class I HLA ( A,B,C) and 6 Class II HLA (DPA1, DPB1, DQA1, DQB1, DRA, DRB1)
Chromosome 6 – the short arm

HLA molecules are proteins and like all other proteins the code or recipe for making them is in the DNA. In particular, HLA are coded by part of chromosome 6. There is huge variation in these genes – they are polymorphic – so there are thousands of possible combinations. Each of us has an almost unique set of HLA. We inherit them in blocks, called haplotypes, from our parents. This means a parent and child will have at least a 50% match. Siblings, however, could be any match between 0 and 100%. 
HLA testing has become increasingly detailed over the years, from testing with serum in the 1950s when they were first discovered, to now using the actual DNA code. To type one person will cost in the region of £700 but considering a transplant will cost between £80,000 and £100,000 then HLA testing is a relatively small outlay. 

HLA – roughly speaking

Now you can see from the diagram that the class I HLA molecule has a chain of alpha polypeptides, called the heavy chain, which is bound outside the cell to a beta-microglobulin, while the part attached to the cell membrane is called the trans-membrane-polypeptide which has a little tail projecting into the cell cytoplasm. 

The alpha polypeptides on the class I HLA are encoded by genes at specific parts of chromosome 6 that have been called HLA-A, HLA-B and HLA-C loci (‘locus’ just means ‘position’, loci is the plural) 

[There are some other codes that will make HLA-G which is used to protect a foetus or baby from the mother, but thats not relevant to this post]
The class II HLA has two polypeptide chains, alpha and beta, each with their own trans-membrane region and tail. 

 These polypeptide chains are encoded by genes in the HLA-DP, HLA-DQ and HLA-DR regions of chromosome 6. 

In the diagram the green box represents the “self” flag while the red box represents the “foreign”. 
The class I and class II molecules are the most immunogenic antigens for rejection in solid organ transplants. 

The most significant one is HLA-DR, followed by HLA-B and HLA-A. So these three loci are the most important for matching donor and recipient.  

Where you live


There is geographical variation in the tests used for HLA typing. 

 In UK the current tests look at the -A,-B,-C,-DR and -DQ but recent research on cross-matching has suggested that up to one third of the positive reactions are caused by antibodies to HLA-DP and so this should be included in the screening protocols. The BTS guidelines in Uk now demand that laboratories are capable of testing for HLA-DP. An updated protocol was introduced in UK in 2006 to reduce some of the inequities of transplant allocation. 

I think in US the loci -A, -B, -C, -DRB1, -DRB3/4/5 and -DQB1 are used for matching for kidney transplants. (Happy to be corrected if someone across the pond knows better). The US also updated their allocation system with respect to HLA, so as to increase the number of minorities receiving organs. 

 It is a slightly confusing area to read about as another source told me that US test for 94 antigens, 25 of them HLA-A, 51 HLA-B and 18 HLA-DR – no mention of -C or -DQ. This same source stated that Europe test for 51 antigens and U.K. for 49 antigens. I guess the bottom line is that laboratories will use different processes and results may not be directly comparable. 



Sensitised?
In the U.K. around 40% patients on the waiting list for a kidney transplant are sensitised to HLA antibodies. This happens with pregnancy, transfusions and previous transplants. Having antibodies can increase the wait. This is what is measured by the “Panel Reactive Antibody” test – sometimes called the Percentage reactive antibody test because results are quoted as a %. These tests are undertaken as a third level of tissue matching, looking for donor-specific antibodies. Historically they were done by mixing donor and recipient samples and waiting to see if one destroyed the other; new methods of virtual cross matching have led to a more accurate assessment of immunological risk.


Of course everyone wants a perfect match 



The survival advantage from a well-matched kidney was established during the 1980s. In 1985 the 10-year survival for the new kidney was 41% if there were no mismatches but 25% if there were some mismatches. Now we are looking at figures of 75% 10 year survival for a well-matched kidney. 

Advances in immunosupression have dramatically increased these figures and now we have a situation whereby having a mismatched living donor is sometimes better than having a well-matched deceased donor organ. This is thought to be because the process of death releases cytokines (chemicals) that damage the kidneys. The age of the donor and the ‘cold ischaemia time’ ( length of time the new kidney is out of a body without a blood supply) is now thought more important that absolute precision in matching.  

Achieving a perfect match may be more important for younger patients because they are quite likely to need a second transplant later in life.  If the kidney was mismatched in the first transplant then of course there will be more antibodies and more difficulty matching for the second transplant.  
There are methods that can be used when a recipient has lots of antibodies – plasmapheresis is like washing the blood to lower the antibodies. But itt is costly and cannot be performed at all centres. It is also possible that antibodies will recur after plasmapheresis. 



Not all HLA mismatches are equal



Some mismatches will be more significant than others. Studies have shown that the major impact comes from -B and -DR antigens. HLA-DR mismatches are correlated with poor long term survival. Another study from Holland has suggested that the combination of mismatches is also relevant, even going so far as describing some combinations as “taboo” combinations that significantly lowered graft survival times. 
It has also been shown that -DR mismatches tend to cause rejection problems within the first six months post-transplant, but -B mismatches lead to problems around 2 years post-transplant. 
A recent study from Perth (Lim et al.)has indicated that -DQ mismatches are associated with acute rejection, independent of the immunosupression used. 

In the end we still need more donors



The fundamental problem with obtaining “the perfect match” is lack of donors. In particular donors from minority ethnic groups are needed, because despite all of the advances, it remains harder to find a match for ethnic minorities and indigenous populations and this is true regardless of the country in question. 

If you thought matching socks was hard….




References
Lim WH, Chapman DR, Coates PT et al. HLA-DQ mismatches and rejection in kidney transplant recipients. Clin J Am Soc Nephrol. 2016 May;11(5):875-83
Williams RC, Opelz G, McGarvey CJ, et al. The Risk of Transplant Failure with HLA Mismatch in First Adult Kidney Allografts from Deceased Donors. Transplantation 2016; 100:1094

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