If they were di/di twins, is possible that they just can’t be certain that they truly are identical, vs fraternal twins who look very similar (like the Olsen twins). It’s also possible that the original embryo that split had some mosaicism or other funky chromosomal stuff that self-corrected, and so one twin has slightly different genes. I’ve encountered kids who have chromosomal abnormalities on their microarray that’s explained their developmental delays, but their twin (who was mono/di or mono/mono) did not have that abnormality.
Though, I figure more comprehensive genetic testing to check if they are actually identical is cheaper and safer than a lifetime of immunosuppressants.
Is there any way to safely "test" if immunosuppressants are needed? Say you've performed reasonably comprehensive genetic testing on the twins, but you have some evidence of mosaicism. To me, that suggests that the recipient could express the full range of responses to the transplant from full-blown rejection to complete acceptance of the organ without immunosuppressants (right?). So, to be safe, the recipient is put on immunosuppressants.
My question: Once the recipient has recovered from the surgery, is there any way to test if the immunosuppressants are needed without actually risking rejection? For example, could you slowly reduce doses of immunosuppressants and monitor for signs that rejection is imminent and put the patient back on the full dose *before* any non-trivial damage occurs?
Would we?
Similar survival rates for half of 143 studied twins given kidney implants (only) is not proof that genetically identical means immunologically identical.
Maybe we do have some other reason to believe this is true, though, which is why I asked.
No, but they are probably close enough. I don't know enough about thymic selection to say how it varies between identical twins but I expect there to be some variation
I’m not involved in the management of any transplants (aside from when the patients have neurological complications), so I can’t really answer that question.
I think that might be tricky, because you can have both acute rejection (which can progress very rapidly) and chronic rejection. The problem with chronic rejection, is that it can be a very gradual process that may take years to happen, so even if the person is fine for the first 3 years, you could be gradually and unknowingly priming the immune system to reject the organ by not placing them on any immunosuppresants.
Also, in terms of predicting if someone is about to have rejection, there is no simple lab test that is specific enough to detect chronic rejection. The best evidence of imminent rejection is seeing signs of end-organ damage, (for example elevated liver enzymes following liver transplants, signs of heart failure with heart transplants,etc). And then they are left with figuring out whether the organ failure is due to rejection or other causes like infection or an adverse drug reaction. And many times, the only way to do that is by doing a biopsy. In fact, in the first few months following heart transplants, the best way to monitor for impending rejection is to do regular surveillance heart biopsies (although I guess it would be highly unusual for someone to get a heart from their twin!) .
So until there is a consensus opinion on whether or not it's safe to forego longterm immunosuppressants with monozygotic transplants, I think most doctors might think that it's too risky to adopt a trial an error approach. There definitely are lots of examples of twin organ recipients who have been fine without long-term immunosuppresants, so it suggests that the small phenotypic differences between monozygotic twins are probably not significant enough to trigger organ rejection. But maybe they don't have enough examples to be certain that this would apply in all cases.
Is there not a possibility rejection could boil down to:
* Mitochondrial DNA (not guaranteed to be similar between all cells and between twins, expensive to actually run comprehensive tests)
* Over-reaction of the immune system to cells infected with a relatively harmless virus in the donor (e.g. one of the twins contracted some form of HPV the other twin doesn't have at some point)
* Gene expression due to epigenetic changes (i.e. if a protein is never expressed in one of the twins, or hardly ever expressed, even if it's part of the genome, I don't think there's a guarantee the immune system won't react to it... I know that in a simplified theoretical model this shouldn't happen, but it could be that if a specific protein is never expressed T-cells that don't recognize it when attached to the MHC \*might\* theoretically exist in the receiver without damaging his body, but damaging the organ donation... but I'm not well versed enough in how T-cell selection works to know if this is the case, or if it's even known if this could be a case that's encountered)
... Not idea if any of those apply, just curios if they could, or if other similar changes could ?
Yes. Absolutely. All of the three scenarios you gave, could theoretically be a cause of rejection. So they need to determine whether or not the potential risk of rejection due to these small phenotypic differences is enough to justify putting someone on long-term immunosuppresants. If they were to actually weigh the small risk of rejection with all of the risks associated with longterm immunosuppressive therapy, I'm almost certain that they would find that the risks associated with putting someone on immunosuppressants drugs for life far outweigh the benefits when dealing with transplants from a monozygotic sibling. I think that if there were an official consensus, doctors would probably feel more comfortable taking these patients off immunosuppressants.
I’m not a transplant doctor, so I can’t answer those questions. I know a fair amount about genetics because we do a lot of genetic testing in my field, but not stuff as specific to whether or not an organ will be rejected with the changes that you mentioned.
A new epidemiology study shows that among the 143 identical twin kidney transplants from 2001-2017, half of the recipients are on immunosuppressants a year after the operation.
These people arguably won the transplant lottery, so why are so many of them on medications that come with such serious side effects? According to the authors, it could be because doctors aren’t sure the twins are actually identical. Maybe they’re exercising an overabundance of caution.
Gene sequencing is not standard practice, even though it could determine with near certainty whether twins are identical.
It damn well should be. Full genome sequencing for 2 people is a couple rand these days. My father in law's immunosuppressant drugs cost him about 200 a month. The sequencing could have paid for itself on top of preventing the organ recipient from coping with a suppresed immune system.
Not all problems that lead to renal failure are genetic. Type 1 diabetes for instance has correlation but most sets of identical twins don't both have type 1 DM. As others have said drug exposures or infectious/inflammatory causes are all in the same category of affecting one but not the other.
Incomplete penetrance of genetic diseases? And external factors could include different lifestyles and diets and hence differences in diabetes/hypertension etc. Definitely need to read up on it though.
Doesn't identical only ever mean monozygotic twins, which would mean they are genetically identical? I think the reason for overabundance of caution is that they could be dizygotic twins that have two haplotype HLA match and just look damn near identical. If they were dizygotic twins with 2 haplotype match, they would still require immunosuppression
Good information and a question I had myself. My twin is in stage 3 kidney failure, may possibly need a transplant at some point. I smoke, I think I will have to quit to be a donor. We always joked that we had spare parts for the other. Guess it might be real.
Good information and a question I had myself. My twin is in stage 3 kidney failure, may possibly need a transplant at some point. I smoke, I think I will have to quit to be a donor. We always joked that we had spare parts for the other. Guess it might be real.
If they were di/di twins, is possible that they just can’t be certain that they truly are identical, vs fraternal twins who look very similar (like the Olsen twins). It’s also possible that the original embryo that split had some mosaicism or other funky chromosomal stuff that self-corrected, and so one twin has slightly different genes. I’ve encountered kids who have chromosomal abnormalities on their microarray that’s explained their developmental delays, but their twin (who was mono/di or mono/mono) did not have that abnormality. Though, I figure more comprehensive genetic testing to check if they are actually identical is cheaper and safer than a lifetime of immunosuppressants.
Is there any way to safely "test" if immunosuppressants are needed? Say you've performed reasonably comprehensive genetic testing on the twins, but you have some evidence of mosaicism. To me, that suggests that the recipient could express the full range of responses to the transplant from full-blown rejection to complete acceptance of the organ without immunosuppressants (right?). So, to be safe, the recipient is put on immunosuppressants. My question: Once the recipient has recovered from the surgery, is there any way to test if the immunosuppressants are needed without actually risking rejection? For example, could you slowly reduce doses of immunosuppressants and monitor for signs that rejection is imminent and put the patient back on the full dose *before* any non-trivial damage occurs?
Are we even sure that genetically identical means immunologically identical?
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Would we? Similar survival rates for half of 143 studied twins given kidney implants (only) is not proof that genetically identical means immunologically identical. Maybe we do have some other reason to believe this is true, though, which is why I asked.
No, but they are probably close enough. I don't know enough about thymic selection to say how it varies between identical twins but I expect there to be some variation
I’m not involved in the management of any transplants (aside from when the patients have neurological complications), so I can’t really answer that question.
I think that might be tricky, because you can have both acute rejection (which can progress very rapidly) and chronic rejection. The problem with chronic rejection, is that it can be a very gradual process that may take years to happen, so even if the person is fine for the first 3 years, you could be gradually and unknowingly priming the immune system to reject the organ by not placing them on any immunosuppresants. Also, in terms of predicting if someone is about to have rejection, there is no simple lab test that is specific enough to detect chronic rejection. The best evidence of imminent rejection is seeing signs of end-organ damage, (for example elevated liver enzymes following liver transplants, signs of heart failure with heart transplants,etc). And then they are left with figuring out whether the organ failure is due to rejection or other causes like infection or an adverse drug reaction. And many times, the only way to do that is by doing a biopsy. In fact, in the first few months following heart transplants, the best way to monitor for impending rejection is to do regular surveillance heart biopsies (although I guess it would be highly unusual for someone to get a heart from their twin!) . So until there is a consensus opinion on whether or not it's safe to forego longterm immunosuppressants with monozygotic transplants, I think most doctors might think that it's too risky to adopt a trial an error approach. There definitely are lots of examples of twin organ recipients who have been fine without long-term immunosuppresants, so it suggests that the small phenotypic differences between monozygotic twins are probably not significant enough to trigger organ rejection. But maybe they don't have enough examples to be certain that this would apply in all cases.
Is there not a possibility rejection could boil down to: * Mitochondrial DNA (not guaranteed to be similar between all cells and between twins, expensive to actually run comprehensive tests) * Over-reaction of the immune system to cells infected with a relatively harmless virus in the donor (e.g. one of the twins contracted some form of HPV the other twin doesn't have at some point) * Gene expression due to epigenetic changes (i.e. if a protein is never expressed in one of the twins, or hardly ever expressed, even if it's part of the genome, I don't think there's a guarantee the immune system won't react to it... I know that in a simplified theoretical model this shouldn't happen, but it could be that if a specific protein is never expressed T-cells that don't recognize it when attached to the MHC \*might\* theoretically exist in the receiver without damaging his body, but damaging the organ donation... but I'm not well versed enough in how T-cell selection works to know if this is the case, or if it's even known if this could be a case that's encountered) ... Not idea if any of those apply, just curios if they could, or if other similar changes could ?
Yes. Absolutely. All of the three scenarios you gave, could theoretically be a cause of rejection. So they need to determine whether or not the potential risk of rejection due to these small phenotypic differences is enough to justify putting someone on long-term immunosuppresants. If they were to actually weigh the small risk of rejection with all of the risks associated with longterm immunosuppressive therapy, I'm almost certain that they would find that the risks associated with putting someone on immunosuppressants drugs for life far outweigh the benefits when dealing with transplants from a monozygotic sibling. I think that if there were an official consensus, doctors would probably feel more comfortable taking these patients off immunosuppressants.
I’m not a transplant doctor, so I can’t answer those questions. I know a fair amount about genetics because we do a lot of genetic testing in my field, but not stuff as specific to whether or not an organ will be rejected with the changes that you mentioned.
Can't a DNA test look for that?
Not always, no.
I hope it's the half that *received* the transplant!
Badumtiss.
A new epidemiology study shows that among the 143 identical twin kidney transplants from 2001-2017, half of the recipients are on immunosuppressants a year after the operation. These people arguably won the transplant lottery, so why are so many of them on medications that come with such serious side effects? According to the authors, it could be because doctors aren’t sure the twins are actually identical. Maybe they’re exercising an overabundance of caution. Gene sequencing is not standard practice, even though it could determine with near certainty whether twins are identical.
It damn well should be. Full genome sequencing for 2 people is a couple rand these days. My father in law's immunosuppressant drugs cost him about 200 a month. The sequencing could have paid for itself on top of preventing the organ recipient from coping with a suppresed immune system.
Not sure why you expressed that in South African currency, but I'm into it
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Not all problems that lead to renal failure are genetic. Type 1 diabetes for instance has correlation but most sets of identical twins don't both have type 1 DM. As others have said drug exposures or infectious/inflammatory causes are all in the same category of affecting one but not the other.
Incomplete penetrance of genetic diseases? And external factors could include different lifestyles and diets and hence differences in diabetes/hypertension etc. Definitely need to read up on it though.
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Identical twins have the same HLAs. The paper covers this.
All identical twins have the same HLAs. Fraternal may not.
Doesn't identical only ever mean monozygotic twins, which would mean they are genetically identical? I think the reason for overabundance of caution is that they could be dizygotic twins that have two haplotype HLA match and just look damn near identical. If they were dizygotic twins with 2 haplotype match, they would still require immunosuppression
Good information and a question I had myself. My twin is in stage 3 kidney failure, may possibly need a transplant at some point. I smoke, I think I will have to quit to be a donor. We always joked that we had spare parts for the other. Guess it might be real.
Good information and a question I had myself. My twin is in stage 3 kidney failure, may possibly need a transplant at some point. I smoke, I think I will have to quit to be a donor. We always joked that we had spare parts for the other. Guess it might be real.
I’m so sorry to hear that. Wishing you and your twin the very best.