A 29-year-old CKD 5 secondary to reflux nephropathy had a kidney offer from her sister, which could be her twin sister. 000 mismatch, FCXM is negative.
- What are the possibilities regarding their genetic relationship?
- How do you plan the immunosuppression?
What are the possibilities regarding their genetic relationship?
Although they have 000 mismatch, they may be monozygotic (share 100% of genetic materials) or dizygotic (share 50% of genetic material). They need meticulous genetic investigation. A variety of methods have been used to identify monozygotic twins, including skin grafting from the potential twin donor to the recipient (the graft would be rejected if the twins were fraternal). Extended blood groups include markers that are determined by many genes on different chromosomes. Analysis of short tandem repeats (STRs) provides a high probability of identifying differences between individuals. 25% of dizygotic twins may have complete HLA identity and falsely considered monozygotic
How do you plan the immunosuppression?
In monozygotic twins:
no need for induction plus minimum dose of immune suppressive drugs with gradual withdrawal.
In dizygotic twins (with 000mismatch, FCXM negative):
managed as low risk patient for rejection with no induction and the maintenance therapy should be individualized according to original disease, risk assessment and post transplant course.
Reference ;
Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
The possibility is either
– Identical twin or
– Fraternal twin with two haplotype matched
The differentiation between identical twins and two-haplotype-matched fraternal twins is important because the
recipient of a transplant from an identical twin requires no immunosuppression. The procedure is immunologically
equivalent to an autotransplantation.
Two-haplotype-matched siblings, whether they are fraternal twins or not, differ in their minor histocompatibility antigens, and immunosuppression is required.
Monozygotic, or identical, twins share a single placenta and amniotic sac at birth. However, such information may be unavailable or unreliable when the patient and donor are evaluated as adults.
A variety of methods have been used to identify monozygotic twins,including skin grafting from the potential twin donor to the recipient (the graft would be rejected if the twins were
fraternal).
Today, several genetic polymorphisms can be exploited to determine identity at many genetic loci providing a high degree of confidence that twins are identical. Extended blood groups include markers that are
determined by many genes on different chromosomes. Analysis of short tandem repeats (STRs), which, as the name
implies, are short nucleotide sequences that are repeated a variable number of times, provides a high probability of
identifying differences between individuals. STRs are often used in monitoring engraftment of HLA-identical bone marrow transplants, so they are exquisite markers of individuality.
Danovitch GM. Handbook of Kidney Transplantation. Sixth Edition, Wolters Kluwer, eISBN 9781496388841, 2017.
may be monozygotic identical twins or two haplotype matched fraternal twins
monozygotic identical twins share same placenta and amniotic fluid it is immunologically
equivalent to an autotransplantation and no need for immunosuppression
two haplotype matched twins need low risk protocols
Hand Book of transplantation
There are two possibilities being 000 mismatch:
1- monozygotic – 000 mismatch occurs 100%
2- Dizygotic – 000 mismatch occurs about 25% chance
The immunosuppressive medications may be applied for 3 months then they may need no more immunosuppressive thearpy provided DSA is negative
Reference:
Gumprich M, Woeste G, Kohlhaw K, Epplen JT, Bechstein WO. Living related kidney transplantation between identical twins. Transplant Proc. 2002 Sep;34(6):2205-6. doi: 10.1016/s0041-1345(02)03202-5. PMID: 12270364.
The donor is her twin sister , we have to exclude congenital vesicoureteric reflux(VUR) , by doing micturating cystourethrogram (MCUG) for the donor , as the prevalence reaches to 50% in siblings of patient with VUR.
The twins either monozygotic or dizygotic, 000 HLA matching is not the diagnostic of the zygosity , as 25 % of siblings can be 000 matching , the confirmed test of zygosity is fingerprinting & short tandem repeats analysis (STR) .
The plan of immunosuppression :
1-In case of monozygotic twin :
high dose of steroids perioperatively because of inflammatory process due to surgery ,no induction , & the maintenance immunosuppressive medications can be individualized according to primary cause of the disease, & the course post operative .
2- in case of dizygotic twin
ooo matching , negative cross match , is considered a low risk, no induction except steroid , & need maintenance immunosuppressive medications .
GENETIC POSSIBILITIES COULD BE DIVIDED INTO IDENTICAL;MONOZYGOTIC OR NON IDENTICA;DIZYGOTIC.PCR BASED SHORT TANDEM REPEATS ANALYSIS INCREASES ACCURACY OF DIAGNOSIS OF MONOZYGOSITY TO AROUND 100%.MONOZYGOTIC TWINS COULD NOT BE GENETICALLY RELATED DUE TO A PHENOMENON OF SOMATIC VARIATION WHICH COULD DEVELOP DUE TO SOMATIC MOSAICISM,CHIMERISM AND EPIGENETIC DRIFT.DIZYGOTIC TWIN TRANSPLANTATION REQUIRE USUAL IMMUNOSUPPRESSION.IN CASE OF MONOZYGOSIS,PERIOPERATIVE STEROID FOR INDUCTION AND 7 DAYS TREATMENT DUE TO AFFECTION OF GENE EXPRESSION CAUSED BY RELEASE OF CHEMOKINES INCLUDING DAMAGE-ASSOCIATED MOLECULAR PATTERNS.IN ADDITION,POSTTRANSPLANT FOLLOW UP INCLUDING RENAL FUNCTION TESTING,PROTEINURIA AND BIOPSY WHEN WORSENING OCCURS WITH IMMUNOSUPPRESSION IF INDICATED.
REFERENCES:
RENAL FELLOW NETWORKIN IDENTICAL TWINS :DO THEY NEED IMMUNOSUPPRESSION? FEBRURARY 10,2016.
JORGENSEN,DR,WU,CMAND HARIHARAN,S:EPIDEMIOLOGY OF END STAGE RENAL FAILURE AMONG TWINSAND DIAGNOSIS,MANAGEMENT,AND CURRENT OUTCOMES OF KIDNEYTRANSPLANTATION BETWEEN IDENTICAL TWINS ;Am J TRANSPLANT,2020:20:761-768
A 29-year-old CKD 5 secondary to reflux nephropathy had a kidney offer from her sister, which could be her twin sister. 000 mismatch, FCXM is negative.
The possibility if they are identical twins with monozygotic inheritance , based on low level of evidence from case reports and case series we can proceed with transplantation by using steroid induction therapy with no further maintenance IS in first year of FU , I’m refereeing to the case report from USA of196 cases and another 12 cases from UK of identical twins kidney transplantation from the period between 1988-2004 they found 70% of them underwent induction with steroid and another 71% they have another minimal IS like low dose CNI in 21% in the first year post transplantation while after one year of FU they reported more than 66% of the patients were off IS with stable graft function and in regards to the patient characteristic in this series they found majority are younger recipients , white ethnicity , less cold ischemic time (< 12 hours), moreover the acute rejection rate from the same series they found no difference in the rate of rejection between patients who are off IS as compared to those on minimal IS , another 5 case series from single center in Spain from 1969 till 2013 longer FU for identical twins kidney transplantation with almost same conclusion with good graft and patient survival and using steroid induction only , but as per recent studies and improvement in our understanding that monozygotic twins are not strictly identical twins and their gene at risk of alteration at any time with the effect of the environmental factors lie ischemic hypo perfusion injury and ischemic injury during surgery so based on this understanding the use of steroid induction IS for monozygotic twins transplant its well acceptable approach.
also we should consider the primary glomerular disease and the risk of recurrence post transplantation as another factor to decide about the type and duration of IS therapy
reference
1-kidney Transplantation in Identical Twins: Do They Need Immunosuppression?
February 10, 2016. Available at :https://www.renalfellow.org/2016/02/10/kidney-transplantation-in-identicaltwins.
2-kidney transplant handbook , 5th edition
1st,: Monozygotic twins occour due to single fertilized ova with single sperm confirmed by having same HLA ,sex ,finger print,blood typing .All of them should be present and no optimal method.their percnt about30%of twins .with this certain informations should be fulfilled about the recepient regarding age, weight,original kidney disease,previous blood tx,pregnancy(senseization).if living monozygotic donor with low risk of sensitization of recepient we can use high dose steroid perioperative with no immunosuppression post tx.
2nd Dizygotic twins resulted from two fertilized ovas.occoured about 70%in twins.
May have same HLA or not.so transplant between them considerd with low risk but not as mono zygotic as their may be Abs against non HLA gene and minor HLA genes so immunosuppression should be considered if 000mismatch with high dose steroid peri operative only with tripple therapy post op.
Steroid,antimetabolite,CNI in 1st 6months then CNI could be withdrawn if white patient.
Refrence
N. Kessaris, D. Mukherjee, P. Chandak, and N. Mamode, “Renal transplantation in identical twins in United States and United Kingdom,” Transplantation, vol. 86, no. 11, pp. 1572–1577, 2008.
View at: Publisher Site | Google Scholar
See in References
Possibilties regarding their genetic relationship: Monozygotic twins
This can be confirmed by Short Tandem Report analysis
Immunosuppression Plan:
Steroids given intraop, up to 2 days post operatively: short course, to reduce the innate immune response that would result from Ischemic reperfusion injury.
There is no optimal immunosuppresive agent, with dose or duration agreed on in transplantation in monozygotic twins. Follow up of these monozygotic twins have shown that some have been placed on maintenance immunosuppresion, and some were not.
Younger recipient age has a higher risk for rejection due to the robust immune system, copmpared to older peole. It is recommended that immunosupperesion in monozygotic twin transplant be individualized.
Reference
Yakubu I et al. Successful renal transplantation between Identical Twins with Very Brief Immunsuppression. Case Rep Transplant. 2018
Nice to see you back Ofonime
Dear All
It was a good start, but feel free to add more contributions especially those who did not contribute much and did not contribute at all.
Challenging clinical scenario at the start of this program
As mentioned by my colleagues It is important in the above scenario to determine zygosity due to the important implication on the transplanted graft and immunosuppression protocol.
1.These twins could be dizygotic (Fraternal) which is more common where 2 separate eggs are fertilized by two different sperms or monozygotic(identical) in which there is one ovum fertilized by 1 sperm.
Common ways to identify zygosity Like similarities in facial and other features can be misleading. other ways include sex(50% of dizygotic twins have the same Sex), blood group(ABO and Rh), HLA(25% of dizygotic twins can be identical in all HLA loci, like the above case if dizygotic). DNA finger printing or reciprocal skin grafts. However, the most accurate with high yield up to 100% is the 13 and 17 short tandem repeat(STR) sequence genetic test.
Monozygotic twins:
Excellent patient and graft survival
Similar patient and graft survival in those who withdrawn immunosuppression compared to those on immunosuppression after 6-12 months and at 5 years those who had no immunosuppression had better patient survival (could be due to calcineurin nephrotoxicity).However, if GN is the primary disease, the recurrence of the initial kidney disease can cause allograft dysfunction and failure(maintenance immunosuppression in these cases should be individualized base on the type and severity of GN at the time of transplantation).
suggested immunosuppression protocol:
No induction or maintenance immunosuppression is required (unless required by a primary immunological cause like SLE) apart from short course of preoperative steroids tapered rapidly to suppress the innate immune system activation from surgical damage and ischemia reperfusion injury due to the release of cytokines and cellular stress during organ recovery. Younger recipients have increased risk of ejection compared to older patients due to robust immune system. If primary GN is the cause(maintenance immunosuppression is controversial and need individualization).
Dizygotic Twins:
We should assess the immunological risk, the above patient has 000 HLA mismatch, FCXM is negative, so there is a low immunologic risk and to be managed like non identical siblings(being low risk, so no induction therapy is required). However, greater number of monozygotic siblings (80%) had reflux when compared with the dizygotic group (35%).this means we need to check the donor first if she had VUR before donation, as the possibility of having the same disease of her sister is high.
Yakubu I., Haririan A., Bartlett S., Sparkes T. Successful Renal Transplantation Between Identical Twins With Very Brief Immunosuppression. Case Rep Transplant. 2018; 2018: 9842893.
Jorgensen DR, Wu CM, Hariharan S. Epidemiology of end-stage renal failure among twins and diagnosis, management, and current outcomes of kidney transplantation between identical twins. Am J Transplant.2020;20:761–768.
Kidney transplantation between a donor and a recipient who have zero HLA mismatches was shown to have better graft outcomes compared to grafts with one or more HLA mismatches. In this scenario case, it can be either monozygotic or dizygotic twins.
Dizygotic or fraternal twins do not have the same DNA as their sibling, so they absolutely require maintenance immunosuppression, as do both human leukocyte antigens (HLA)-matched and -mismatched living and deceased donor kidney recipients.
If monozygosity has been identified, then there is no need for induction immunosuppression apart from high dose steroids at the perioperative period, however, the decision to stop or minimize immunosuppressive medications should be individualized according to the primary disease and the post-transplant course.
-monozygose or dizygose
If mono no need for induction
And can use cortisol free protocol
If dizygose can use basiliximab no need for ATG or use solumedrol pulse alone
and minimal dose of immunosuppressant
-should exclude VUR in her sister by ctut and retrograde pyelogram
The possibilities are ; 1. Identical twins or 2. Non-identical twins
In case of identical twins , there is no need for immunosuppression at all because of HLA match between them . The common example is in the history of transplantation 1954, Prof Joseph Murray transplanted identical twin brother at Brigham Hospital ,USA. Non- identical twins on the other hands they need maintenance immunosuppression but no need for induction therapy. This because of HLA can be different at the levels of small protein particles e.g. EPLETS/ TRIPLETS and some of these differences and can be enough to induce rejections and therefore, need for maintenance therapy.
Nice to see your contribution Ben.
Thank you all for your wonderful contributions.
Thnxs prof
Genetic relationship may be identical twins that mean monozygotic or dizygotic twins.
We need minimal immunosuppressive drugs as they had zero mismatch and negative cross match
A 29-year-old CKD 5 secondary to reflux nephropathy had a kidney offer from her sister, which could be her twin sister. 000 mismatch, FCXM is negative.What are the possibilities regarding their genetic relationship?
The possibilities are either:
1- Monozygotic (share 100% of genetic material, the HLA mismatch will be 000)
2- Dizygotic (share 50% of genetic material, the chance of 000 HLA mismatch is 25%.
1/3 of the twins are monozygotic, 2/3 are dizygotic twins.
Monozygosity of twins can be proved by DNA fingerprinting {buccal smear DNA PCR amplification using STR (short term repeat) profiling for genetic alleles}.
How do you plan the immunosuppression?Do you have evidence that they should be considered differently compared to the White race? For example, rejection could be aggressive in a certain race
CNI levels could vary across races.
A- If no history of sensitization, and monozygotic twins:
No induction
Maintenance immunosuppression (CNI+ MMF/MPA/AZA+ Steroid)
for 1 to 3 months, and then stop (1,2,3)
B- If no history of sensitization, and dizygotic twins or non-twin sibling:
No induction
Immunosuppression: According to race
If White recipient – CNI+ MMF/MPA/AZA+ Steroid for 3-6 months, then stop CNI but continue MMF/MPA/AZA and steroid (4)
C- If African-American: low dose CNI+ MMF/MPA/AZA+ Steroid.
D- If history of sensitization present, manage as high risk and give induction with rabbit ATG followed by CNI+ MMF/MPA/AZA+ Steroid.
The above-mentioned patient is managed as low risk patient (MM 000, FCXM negative) for rejection with no induction.
Twins are two types :
monozygotic twins(identical twins) who are sharing the same DNA resulting from fertilization of single ovum , so they are similar in sex but this type not common like other type .
Dizygotic twins (Fraternal twins ) who are not sharing the same DNA and they developed from fertilization of two different ovums with two different sperms , so they are different in sex .
differentiation between identical and fraternal twins by shape may facing difficulties due to environmental factors especially when they are same sex , so must confirm monozygocity by 13/17 Short Tandem Repeat Sequences (STR) on few regions of DNA…….
Regarding immunosuppression :
-Dizygotic twins :
*If there is no history of sensitization:
No need for induction
Immunosuppression: According to race
In White patients : triple therapy (Steroid+CNI+ Antimetabolite )for 3-6 months, then stop CNI and continue on double therapy antimetabolite and steroid
In African-American: use triple therapy ( Steroid+CNI+ Antimetabolite )
*If there is history of sensitization :
To be managed as high risk patients ( give induction with ATG followed by triple therapy ( Calcineurin inhibitor+ Antimetabolite+ Steroid).
In monozygotic twins : no need for induction and give maintenance immunosuppression for 1-3 months then stopped unless indicated if the primary disease was autoimmune and high possibility for recurrence
1.
The first successful trial in kidney transplantation between identical twins was performed in 1954 by Prof. Joseph Murray, an American surgeon who won Nobel Prize in Physiology or Medicine 1990 for his invention in transplantation.
Twins may be monozygotic or dizygotic. Monozygotic twins have 0% difference in genetic material, while dizygotic twins share about 50% of DNA.
Complete matching of HLA typing is not enough to judge on monozygosity, as it may present in dizygotic twins in about 25%. Therefore, it is recommended to use short tandem repeat (STR) analysis for accurate identification of monozygotic twins in addition to other factors like sex, blood grouping and HLA matching.
Accurate analysis of DNA of the twin to find out whether a monozygotic or dizygotic is an essential step in decision of induction therapy and determining the method of administration of immunosuppressive drugs in terms of magnitude, dose and duration.
Presumptive monozygotic twins have an excellent survival rate for the recipient and the graft. Kessaris et reported most of them received post transplantation immunosuppressive drugs.
Jorgensen et found that only 50 % of identical twins receive immunosuppressive drugs without statistical difference in graft survival with those who did not receive these drugs. Graft survival was lower in glomerulonephritis patients than other causes of renal failure.
2.
Plan of immunosuppression
No induction therapy or maintenance immunosuppressive drugs ( unless indicated as in autoimmune diseases (SLE for example)
Steroid may be given for the first week
Idris Yakubu et al recommend to use the lowest dose of immunosuppressive therapy in the perioperative time and discontinuing them 2 or 3 weeks after operation.
☆ Reference
• Jorgensen, DR, Wu, CM, Hariharan, S. Epidemiology of end-stage renal failure among twins and diagnosis, management, and current outcomes of kidney transplantation between identical twins. Am J Transplant. 2020; 20: 761– 768. https://doi.org/10.1111/ajt.15638
• Idris Yakubu, Abdolreza Haririan, Stephen Bartlett, Tracy Sparkes, “Successful Renal Transplantation between Identical Twins with Very Brief Immunosuppression”, Case Reports in Transplantation, vol. 2018, Article ID 9842893, 5 pages, 2018. https://doi.org/10.1155/2018/9842893
• Kessaris N, Mukherjee D, Chandak P, Mamode N. Renal transplantation in identical twins in United States and United Kingdom. Transplantation. 2008;86(11):1572-1577.
-Monozygous twins might received minimal or no immunosuppression to preserve consistent allograft function
-After the immune system has been sufficiently suppressed following the initial inflammatory response associated with kidney transplantation surgery, the next step would be to reduce or discontinue maintenance IS with extreme caution, taking into account the postoperative course, primary disease, and pathological graft outcomes. As an induction IS, our patient received mainly greater dose of steroids.
-HLA typing, blood typing, chorionicity, placental assessment after birth, (DNA) finger printing, and reciprocal skin grafting have all been used to determine monozygosity.
-The patients were given a brief course of steroids to reduce the innate immune response caused by ischemia-reperfusion damage, which has been linked to graft rejection.
References
-Kidney Transplantation in Identical Twins: Do They Need Immunosuppresion?
February 10, 2016. Available at :https://www.renalfellow.org/2016/02/10/kidney-transplantation-in-identica/ (Accessed 5/11/2021)
-Yakubu, I., Haririan, A., Bartlett, S. and Sparkes, T., 2018. Successful Renal Transplantation between Identical Twins with Very Brief Immunosuppression. Case reports in transplantation, 2018..Available at :https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040249/ (Accessed 5/11/2021)
What are the possibilities regarding their genetic relationship?
A pair of donor-recipient having 000 mismatch. This could be seen in siblings, who may or may not be twins.
Among siblings (who might be twins), there is 25% chance of having same HLA haplotype (000 mismatch) inheritance.
Twins can be either monozygotic (identical, from a single embryo) or dizygotic (2 separate sperms and 2 separate ova).
So in monozygotic twins, the HLA mismatch will be 000. But in dizygotic twins, the chance of 000 mismatch is 25%. One third of the twins are monozygotic, two-thirds are dizygotic twins.
In this case, the sisters could be monozygotic twins, or dizygotic twins, or could be siblings but not twins.
For confirming the genetic relationship, further information is required like:
a) Age: if different, rules out that they are twins
b) gender: if different, then dizygotic twins (if age same)
c) blood group: if different, then dizygotic twins (if age same)
But if age, gender, blood group are same, still they can be dizygotic twins.
Monozygosity of twins can be proved by DNA fingerprinting {buccal smear DNA PCR amplification using STR (short term repeat) profiling for genetic alleles}.
How do you plan the immunosuppression?
Planning immunosuppression involves detailed history, examination and information regarding zygosity of the donor-recipient pair.
If no history of sensitization, and monozygotic twins:
No induction
Maintenance immunosuppression (Calcineurin inhibitor+ Antimetabolite+ Steroid)
for 1 to 3 months, and then stop (1,2,3)
If no history of sensitization, and dizygotic twins or non-twin sibling:
No induction
Immunosuppression: According to race
If White recipient – Calcineurin inhibitor+ Antimetabolite+ Steroid for 3-6 months, then stop Calcineurin inhibitor but continue antimetabolite and steroid (4)
If African-American: low dose Calcineurin inhibitor+ Antimetabolite+ Steroid (5)
If history of sensitization present, manage as high risk and give induction with rabbit antithymocyte globulin followed by Calcineurin inhibitor+ Antimetabolite+ Steroid.
As Flow cytometry cross match is negative in this patient, it is unlikely that she is a high risk patient and induction therapy need not be given
References:
1) Murray JE, Merrill JP, Harrison JH. Renal homotransplantation in identical twins. 1955. J Am Soc Nephrol 2001;12(1): 201
2) Weil R 3rd, Starzl TE, Porter KA, et al. Renal isotransplantation without immunosuppression. Ann Surg. 1980;192:108.
3) Krishnan N, Buchanan PM, Dzebisashvili N, et al. Monozygotic transplantation: concerns and opportunities. Am J Transplant. 2008;8:2343
4) Aydingoz SE, Takemoto SK, Pinsky BW, et al. The impact of human leukocyte antigen matching on transplant complications and immunosuppression dosage. Hum Immunol. 2007;68:491.
5) Ojo AO, Port FK, Held PJ, et al. Inferior outcome of two-haplotype matched renal transplants in blacks: role of early rejection. Kidney Int. 1995;48:1592
Theoretically identical twins are 100% genetically matched, but we cannot overlook the intrauterine gene mutation and environmental effect that may cause phenotypic and genotypic divergence between twins, I mean epigenetic changes. However, we have some studies that display there isn’t any significant difference between identical twins kidney transplant outcome with and without immunosuppression therapy.
In a study was published in 2020 in American journal of transplantation, among identical twins transplant, excellent kidney graft and patient survival were reported and approximately 50 percent of patients haven’t been received any immune suppression and no difference in graft survival was found among patients with and without immunosuppression.
In this study, monozygosity between twins was confirmed by concordance in sex, blood type and HLA antigen match with precision testing using short tandem repeat sequencing (STR) DNA to a likelihood of nearly 100%.
In another study that evaluate identical twins kidney transplant from 1969 to 2013, concluded that kidney transplantation from living monozygotic twin is associated to outstanding graft outcome without immunosuppression, and immunosuppressive therapy is probably unnecessary.
The recipient of kidney allograft from identical twin, merely need corticosteroid for induction therapy and no need to thymoglobulin. Corticosteroid can be continued for one week.
Since recurrence of glomerulonephritis is a concern, Antimetabolites and CNIs for maintenance therapy, should be considered when required for other immunological disease such as SLE and other glomerulonephritis.
They may be monozygotic (share 100% of genetic material) or dizygotic twins ( share 50% of genetic material)
they should be differentiated by DNA analysis, multilocus DNA fingerprinting and 13 or 17 short tandem repeats analysis
zygosity may be assumed from HLA typing but 25% of dizygotic twins may have complete HLA identity and falsely considered monozygotic
in monozygotic twins:
in dizygotic twins (with 000mismatch, FCXM negative):
TWIN
There are different types of twins:
Monozygotic twins:
Monozygotic twins that develop from a single fertilized ovum have the same genetic makeup and, consequently, are of the same gender and strikingly resemble each other physically, physiologically, and mentally.However, they may develop some genetic differences after the zygote splits, due to mutations in the DNA.
Recent studies have shown that monozygous twins are not genetically-related due to the phenomenon of somatic variation, which can arise from three different mechanisms:
Identical Twins (monozygotic) Don’t Need Immunosuppression After Transplant,HOWEVER ..”Some transplant physicians are not comfortable managing a patient without immunosuppression, so they tend to give at least some form of immunosuppressant therapy,”MEDSCAPE.
So, should monozygous twins receive any induction or maintenance IS?
Dizygotic Twin:
Dizygotic are twins which result from the fertilization of two different eggs with two different sperms. They are genetically like siblings, sharing about 50% of the genes. Each fetus lies within its own two membranes (chorion and amnion) and they do not share blood vessels. All dizygotic twins have two membranes each (dichorionic-dizygotic) and two placentas, though occasionally the placentas attach. Dizygotic twin pairs can be girl/girl, boy/boy, or girls/boy. Dizygotic or fraternal twins are non-identical.
Regarding IS Dizygotic twins may be managed the same as those with low rate for rejection (+/- induction therapy )and maintenance therapy.
Polar body Twins :
Polar body twins happen very rarely, and they result from one egg fertilized by two different sperm. Polar body twinning would result in “half-identical” twins.
Regarding IS and induction can be managed the same way as Dizygotic twin.
Please do not post your reply twice. It will be discounted.
Twins are
Momozygote twins (identical twin represent 0.33%)
Dizygote twins (fraternal)
Dizygotic twins share about 50% of their DNA with siblings. The probability to have a 2 haplo-match is 25%
renal transplantation between visible MZ twins. needs to perform zygosity testing using STR short tandem repeats test to diagnose monozygotic twins.
The immune homology is not the sole player in graft rejection. Trauma, ischemia, and reperfusion during organ transplantation stimulate cytokines release, activate the immune response, and participate in graft rejection. to prevent this cascade steroid, need to be used in MZ twins preoperatively regardless of the genetic base. native disease recurrence as GN is an important reason for graft loss in HLA-identical sibling transplants so steroids will benefit to prevent a recurrence.
data to guide immunosuppressive therapy is scanty but a wise approach would include the use of steroids with CNI after transplantation thereafter; the cautious reduction and even withdrawal of the immunosuppression should be possible once the inflammatory response associated with the surgery has resolved.
References:
· Day, Elizabeth1,5; Kearns, Patrick K.1; Taylor, Craig J.2,3; Bradley, J. Andrew3,4 Transplantation Between Monozygotic Twins, Transplantation: September 15, 2014 – Volume 98 – Issue 5 – p 485-489 doi: 10.1097/TP.0000000000000274
· orgensen DR, Wu CM, Hariharan S. Epidemiology of end-stage renal failure among twins and diagnosis, management, and current outcomes of kidney transplantation between identical twins. Am J Transplant [Internet]. 2020 Mar 1;20(3):761–8. Available from: https://doi.org/10.1111/ajt.15638
1- If they are twins , they may be either monozygotic or dizygotic
As they are of the same sex and HLA mismatch is 000 so they are mostly monozygotic but further confirmation using genetic test and 13 or 17 Short Tandem Repeat sequencing is needed. In case of dizygotic twin , they may have the same sex in 50% of cases and share the same two haplotypes in 25 % of cases (Jorgensen D et al .,2020).
2- Regarding immunesuppression treatment
A- Step 1 : Immunological risk assessment through assessing HLA mismatch , cross match CDC and presence of DSA by PRA
Immunological of this patient is low as HLA mismatch is 000 , negative cross match and the cause of her ESRD isn’t GN , so is at low immunological risk .
B- Step 2 : confirm monozygosity
TWIN
There are different types of twins:
Monozygotic twins:
Monozygotic twins that develop from a single fertilized ovum have the same genetic makeup and, consequently, are of the same gender and strikingly resemble each other physically, physiologically, and mentally.However, they may develop some genetic differences after the zygote splits, due to mutations in the DNA.
Recent studies have shown that monozygous twins are not genetically-related due to the phenomenon of somatic variation, which can arise from three different mechanisms:
Identical Twins (monozygotic) Don’t Need Immunosuppression After Transplant,HOWEVER ..”Some transplant physicians are not comfortable managing a patient without immunosuppression, so they tend to give at least some form of immunosuppressant therapy,”MEDSCAPE.
So, should monozygous twins receive any induction or maintenance IS?
Dizygotic Twin:
Dizygotic are twins which result from the fertilization of two different eggs with two different sperms. They are genetically like siblings, sharing about 50% of the genes. Each fetus lies within its own two membranes (chorion and amnion) and they do not share blood vessels. All dizygotic twins have two membranes each (dichorionic-dizygotic) and two placentas, though occasionally the placentas attach. Dizygotic twin pairs can be girl/girl, boy/boy, or girls/boy. Dizygotic or fraternal twins are non-identical.
Regarding IS Dizygotic twins may be managed the same as those with low rate for rejection (+/- induction therapy )and maintenance therapy.
Polar body Twins :
Polar body twins happen very rarely, and they result from one egg fertilized by two different sperm. Polar body twinning would result in “half-identical” twins.
Regarding IS and induction can be managed the same way as Dizygotic twin.
Thanks, Assafi for this new information about the Polar Body Twins.
Dear All
Please read Dr Assafi comment
The possibilities are either monozygotic vs Dizygotic twins, therefore the first part is confirming homozygosity first (to confirm Monozygosity we will need short tandem repeat (STR) analysis to confirm identical all 16 polymorphic gene loci between both sisters)
If Dizygotic then the are 000 mismatch, but still different therefore they will be treated as low-risk transplant and accordingly, I will proceed with transplant according to the local protocol
If Monozygotic then it might e tricky and I will explain why
Despite the fact that monozygotic identical twins renal transplant might be a rare opportunity to use minimal immunosuppression, there is still a possibility of discordant protein presentation in identical twins that could trigger alloimmune response and lead to graft injury. Therefore optimal immune suppression planning is warranted. Due to lack of evidence and rarity of the situation then the evidence in the literature will be based on case reports only.
My plan would be
· Check for FXCM and DSA
· Confirming Monozygosity then my immunosuppression would be
A 3-day steroid taper course consisting of methylprednisolone 500 mg intraoperatively, followed by 250 mg and 125 mg intravenously on POD 1 and 2, respectively. Then stop immunosuppression and given the very short course of immunosuppression and no Induction or long-term maintenance then no need for PCP or CMV prophylaxis.
Again this will need frequent monitoring and the plan might change at any point depending on the graft function and short and long term follow up
simply, both sisters can be monozygotic or dizygotic twins. if dizygotic, they can still 000 mismatch as HLA matching is for the major gene types, not the smaller subtypes, and immunosuppression is needed as usual for live related transplant. if monozygotic, immunosuppression is still needed but less intensive, usually with 2 agents of only maintenace ttt without induction therapy, usually MMF and steroids because the failed kidney can develop some de novo gene exposure with the cumulative triggers of pathogenesis. in our centre, we did successfully kidney transplant for monozygotic twins and the maintenance ttt was as I mentioned before
In this case scenario the two sisters could be identical twins or not.
Dizygotic twins came from fertilization of 2 ova by 2 sperms, having half of the genetic material same as other Siblings from different pregnancies. There is a small chance of having 100% match in their HLA.
Dizygotic twins can be managed as any sibling and need to be maintained on immunosuppression .
On the other hand , Monozygous twins come from a single ovum fertilized by one sperm.Identical twins share almost every single feature starting from the genes including those encoding the HLA antigens so they share the genotype. This must be confirmed by genetic testing of their DNA using PCR Based short tandem repeat analysis with other methods such as HLA typing and blood groups for sure .
In case of monozygotic twins there are various protocols.
DAMPs (damage-associated molecular patterns), along other chemokines, are released during ischemia-reperfusion injury and cellular stress. That’s an important point justifying induction and IS by many centers.
Many transplanted identical twins had immunosuppression for at least a year as
their medical staff feel unsafe to leave them without immunosuppression especially if the original cause of renal failure was GN or unknown cause.
Some studies showed no difference in graft survival at 6 months, 1 year and 5 years between immunosuppressed group and that which didn’t receive any.
Individualization and tailoring the plan is the key here.
Infections, Malignancies, HTN, Diabetes, CVD, Age and original kidney disease all should be put into consideration in taking the decision of whether to immunosuppress identical twins or not, and if yes, what’s the protocol, and for how long.
In this case, I believe I would go with no induction, steroids , early withdrawal, and protocol biopsy.
Renal transplantation between monozygous twins can require minimal immunosuppression thereby reducing the toxicities of immunosuppressive therapy. On the other hand there is a possibility of discordant protein presentation in identical twins that could trigger alloimmune response and causes graft injury. The immunosuppression can be withdrawn safely and rapidly in selected monozygous identical twin renal transplant recipients,meanwhilw this has to be individulaised according to confirmimh momzygotic twins and possibility of primary disease recurrence(1)
The optimal method of determining monozygosity is unclear, including HLA typing, blood typing, chorionicity, evaluation of placenta after birth, (DNA) finger printing, and reciprocal skin grafting . Short tandem repeat (STR )analysis has been shown to provide a greater sensitivity and precision in identifying differences between identical twins .(2)
In an Organ Procurement Transplant Network (OPTN) database study, Krishnan et al. evaluated the use of immunosuppressive agents at discharge and 6 months and 1, 2, and 3 years after transplant in identical twin kidney transplant recipients. And concluded that recipient and graft survival rates were the same from the time of transplant up to 5 years between those who received immunosuppression at discharge and those who did not (3)
The optimal immunosuppressive agent, magnitude, and duration of immunosuppression after monozygotic twin kidney transplantation remain controversial(4)
-Steroids perioperatively can be used to prevent rejection due to possible activation of innate immune response due to ischemic reperfusion injury, with posttransplant monitoring.
1-Yakubu I etal., Successful Renal Transplantation between Identical Twins with Very Brief Immunosuppression. Case Rep Transplant. 2018; 2018: 9842893.
2- Krishnan N., Buchanan P. M., Dzebisashvili N., Xiao H., Schnitzler M. A., Brennan D. C. Monozygotic transplantation: Concerns and opportunities. American Journal of Transplantation. 2008;8(11):2343–2351. doi: 10.1111/j.1600-6143.2008.02378.x.
3- Krishnan N., Buchanan P. M., Dzebisashvili N., Xiao H., Schnitzler M. A., Brennan D. C. Monozygotic transplantation: Concerns and opportunities. American Journal of Transplantation. 2008;8(11):2343–2351.
4-Hauch A., Heneghan J., Killackey M., et al. Living-related kidney transplant in two sets of HLA-identical twins. Journal of Surgery and Transplantation Science. 2013;1(1, article 1003)
transplantation between the twins even in identical (monozygotic) has not been complete successful. Analysis of the brigham experiences of 30 identical twins renal transplantation showed only around 65% patient survival rate and 55% graft survival rate at 25 year follow up. European Dialysis and Transplantation association Registry reported among 41 renal transplantations between identical twins: 24 had renal failure due to glomerulonephritis, 36 were alive with functioning kidney 1 to 14.5 years.
In a study of 120 identical twin renal transplant recipients in the United States (US) and 12 recipients in the United Kingdom (UK), 68% and 33% of patients, respectively, were discharged on some form of immunosuppression, with steroids being the most commonly used agent in both groups . At various follow-up time points, fewer patients were on each immunosuppressive agent. This suggests that, in some patients, immunosuppression was only given for a short period of time after transplantation. However, the timeframe of discontinuation of immunosuppression was not reported, and it is unclear if all cases were truly monozygotic identical twins, although the 5-year graft survival rate among those who received immunosuppression was numerically better compared to those who did not.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6040249/#sec3title
As regard to kidney transplantation between twins, must firstly consider important types of twins which related to kidney transplantation?
Fraternal twins (two haplotype matched) or dizygotic are ,essentially two ordinary siblings who happen to be born at the same time ,since they arise from two separate eggs fertilized by two separate sperms , just like ordinary siblings this is the most common type of twins.
Identical twins or monozygotic arise from single ovum fertilized by a single sperm
They are genetically identical but phenotype show difference related to environmental influence .
The differentiation between identical twins and fraternal twins is important because the
recipient of a transplant from an identical twin requires no immunosuppression. The procedure is immunologically equivalent to an auto transplantation. Two-haplotype-matched siblings, whether they are fraternal twins or not, differ in their minor histocompatibility antigens, and immunosuppression is required. Monozygotic, or identical, twins share a single placenta and amniotic sac at birth. However, such information may be unavailable or unreliable when the patient and donor are evaluated as adults. A variety of methods have been used to identify monozygotic twins,
including skin grafting from the potential twin donor to the recipient (the graft would be rejected if the twins were fraternal). Nowadays, several genetic polymorphisms can be exploited to determine identity at many genetic loci providing a high degree of confidence that twins are identical. Extended blood groups include markers that are
determined by many genes on different chromosomes.
References:
Genetics, Structure and Function
Bjorkman PJ, Saper MA, Samraoui B, et al. Structure of the human class l histocompatibility antigen, HLA-A2. Nature 1987;329:506-512.
Germain RN, Margulies DH. The biochemistry and cell biology of antigen processing and presentation. Annu Rev Immunol 1993;11:403-450.
Parham P, Adams EJ, Arnett KL. The origins of HLA-A,B,C polymorphism. Immunol Rev 1995;143:141-180.
The MHC Sequencing Consortium. Complete sequence and gene map of a human major histocompatibility complex. Nature
1999;401:921-923.
Nomenclature Holds worth R, Hurley CK, Marsh SGE, et al. The HLA Dictionary 2008: a summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and
their association with serologically defined HLA-A, -B, -C, -DR and -DQ antigens. Tissue Antigens 2009;73:95-170.
Marsh SG. Nomenclature for factors of the HLAsystem, update September 2015. Tissue Antigens 2015;86(6):469-473.
HLA Typing Erlich H. HLADNAtyping: past, present, and future. Tissue Antigens 2012;80(1):1-11.
Terasaki PI, McClelland JD. Microdroplet assay of human serum cytotoxins. Nature 1964;204:998-100.
1.immunosuppression can be safely withdrawn in monozygotic identical twin transplant recipients.
2.immunosuppression withdrawal or minimization in this patient population needs to be individualized, and several important factors need to be included confirmation of true monozygosity using reliable methods and analysis of the risk versus benefit of immunosuppression, including the likelihood of primary disease recurrence.
3.use of steroids perioperatively to prevent rejection resulting from activation of innate immune response due to ischemic reperfusion injury, along with close posttransplant monitoring
Dear All
Many of you illuded to race-adjusted immunosuppression. For example, African American, Asian, African Arab.
Do you have evidence that they should be considered differently compared to the White race?
For example, rejection could be aggressive in a certain race
CNI levels could vary across races.
sir black receipients,aboriginals have shown a decreased bioavailability of CNIs,high rate of acute rejection and decreased graft survival among recipients of different races at 6 years before the year 2000.but with thymoglobulin induction and maintenance with tacrolimus/MMF no difference in graft survival among different races is seen nowadays.
Am J Nephrol 2009;29:327–333 DOI: 10.1159/000163558
1) twins can be either dizygotic(fraternal) or less commonly monozygotic(maternal or identical).calculation of preliminary probability of monozygosity among twin births can be done by heritable factors like sex,blood group and HLA match.confirmatory testing of zygosity is done by using 13 or 17 STR sequence genetic tests.dizygotic twins do not have identical DNA but ahre roughly 50% of their DNA with their siblings.Probability of dizygotic twins having the same sex is 50%.probability of dizygotic twins sharing a 2 haplo match is 25%.probability of dizygotic twins sharing the same blood group depends on parental blood types and varies from 6.25% to 100%.probability of monozygosity in twins having the same sex,blood group and 2 haplo match matches is 93.75%.concordance in all STR loci among the suspected twin pair increases the likelihood that a pair is monozygotic to nearly 100%.
but recent studies have shown that monozygous twins may not be genetically similar due to the phenomenon of somatic variation which can arise from somatic mosaicism,chimerism and epigenetic drift.hence close post transplant monitoring and dsa testing if elevation in sr creatinine is noted along with biopsy to be done.
2) > 60 year old
no induction
methylprednisolone 500mg D0, 250mg POD 1,125 mg POD 2 then stop.
no maintenance.
18-60 year old
no induction
methylprednisolone 500mg D0,500mg D1,250 mg D2 and D3,125mg D4,D5,D6
Receipients with primary immunological kidney disease like SLE ,Methylprednisolone as for 18-60 yr old with maintenance prednisolone 5-7.5mg/day and MMF 1-2g/day for 3 years and then omit if no recurrence till then.
https://doi.org/10.1111/ajt.15638
Kidney transplantation in the African American population was traditionally considered a procedure with high immunological risk due to the associated higher incidence of acute and chronic rejection and the inferior graft outcome compared to other ethnic groups (1). Several studies have shown that African American recipients have immune hyper-responsiveness, more HLA polymorphisms, in addition to several important cytokine polymorphisms (2).
Additionally, some modifiable risk factors for poor allograft outcomes like time on dialysis pretransplantation, diabetes, and access to medical care are more common in African American population (3).
References:
1) Haririan A, Sillix DH, Morawski K, et al. Short-term experience with early steroid withdrawal in African-American renal transplant recipients. Am J Transplant. 2006 Oct;6(10):2396-402.
2) Taber DJ, Hunt KJ, Gebregziabher M, et al. A Comparative Effectiveness Analysis of Early Steroid Withdrawal in Black Kidney Transplant Recipients. Clin J Am Soc Nephrol. 2017 Jan 6;12(1):131-139.
3) Eckhoff DE, Young CJ, Gaston RS, et al. Racial disparities in renal allograft survival: a public health issue?. J Am Coll Surg. 2007 May; 204(5): 894-902; discussion 902-3
African American transplant recipients have a higher risk of allograft failure and have shorter graft half-lives than white patients which shown by few studies in US.
Study have shown that African Americans are more likely to be presensitized to HLA. In vitro studies have shown that immune hyperresponsiveness in blacks is more likely to result in graft failure.
Secondary analyses of drug efficacy studies have shown that higher doses of tacrolimus and mycophenolate mofetil were required in African Americans to match with rejection rates similar to the whites. Recent data from a study found that black patients are more likely to have cytochrome P450 3A5 polymorphisms. They required higher tacrolimus dosing to achieve therapeutic drug concentrations but doses of drugs generally required to achieve therapeutic level, which might not explain why there is differences in short or long term graft survival.
REFERENCES
First MR, Schroeder TJ, Monaco AP, Simpson MA, Curtis JJ, Armenti VT. Cyclosporine bioavailability: dosing implications and impact on clinical outcomes in select transplantation subpopula- tions. Clin Transplant 1996; 10: 55–59.
Neylan JF. Immunosuppressive therapy in high-risk transplant patients: dose-dependent efficacy of mycophenolate mofetil in African-American renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation 1997; 64: 1277–1282.
Neylan JF. Racial differences in renal transplantation after im- munosuppression with tacrolimus versus cyclosporine. FK506 Kidney Transplant Study Group. Transplantation 1998; 65: 515– 523.
Study by Ojo et al pointed to increased acute rejection episodes in 2 haplotype match living related donors in African-american recipients as compared to whites (13.2% vs 7.4%) leading to worse 5 year graft survival (50% versus 76%). It could be related to pharmacokinetics of CNI in African-Americans.
Reference:
1) Ojo AO, Port FK, Held PJ, et al. Inferior outcome of two-haplotype matched renal transplants in blacks: role of early rejection. Kidney Int. 1995;48:1592
Thanks, Amit
But Ojo et al was in 1995. The situation could be different now. Any update?
In a study by Oliver et al, there was no difference in outcomes among a cohort of department of defense patients on the basis of race/ ethnicity.
Oliver III JD, Neff RT, Leeser DB, et al. Influence of race on kidney transplantation in the department of defense healthcare system. Am J Nephrol 2009;29:327-333.
Blacks are nearly four times more likely than Caucasians to develop kidney failure requiring dialysis or renal transplant (1).
Asian recipients had the highest graft survival, followed by Whites, and Blacks had the lowest graft survival.(2)
Because the curve for graft survival for Blacks over time violated the proportional hazards assumption (at 6 years post-transplant), analysis was segregated into two segments. Through 6 years of follow-up, graft survival was 77% for Blacks and 81% for non-Blacks . Through 9 potential years of follow-up, graft survival for Blacks was 56% and 78% for Whites .
This was consistent with the observation that a period effect in the year 2000 (the change of regimen to 100% thymoglobulin induction and MMF maintenance for all Black patients), in a setting of equal access to care, including medications, was associated with attenuation of the disparity in graft outcomes for Blacks versus Whites. Most patients received tacrolimus with rapid steroid taper (complete withdrawal at 6 weeks).
1.
US Renal Data System. Bethesda, National Institute of Health, NIDDK, 2005.
2-
Opelz G, Mickey MR, Terasaki PI: Influence of race on kidney transplant survival. Transplant Proc 1977;9:137–142.
External ResourcesPubmed/Medline (NLM)Chemical Abstracts Service (CAS)ISI Web of Science
Monozygous twins come from a single fertilized ovum by one sperm, and studies have proved that monozygous twins are not genetically-related due to the mechanism of somatic variation, which can be caused by
Somatic mosaicism occurs in early embryo development and results in tissues having varying genetic expression arising from a single zygote through numerous mechanisms such as heteroplasmy (unequal division of mitochondrial DNA within the cellular cytoplasm) and uniparental disonomy (where both copies of a chromosome or genomic region are inherited from a single parent)
Chimerism occurs after introduction of external genetic element either from mother or inter-embryonic during pregnancy .
Epigenetic drift environmental alteration of the genetic content (early in utero and lifestyle).
So, regarding induction therapy in Tx :no randomized controlled trials the value of using it . but still there are a few reports where patients received minimal or no immunosuppression. If you would chose off IS protocol better to be in carefully selected patients(,younger, White, and had a cold ischemia time of less than 12 hours).
In regards to rejection rates in kidney transplantation in identical twins in the US and United Kingdom during 1988 and 2004, they noticed no significant risk of rejection between IS group and off IS group :however there were a noticeable diiference in the recurrence of the the 1 ry disease and side effect of IS .
In other study : reported good outcomes at one and five years. Recipients received only a single dose of high dose steroids intraoperatively and no maintenance IS. .
DAMPs (damage-associated molecular patterns), among other chemokines, are released during ischemia-reperfusion injury and cellular stress during organ recovery which may modify gene expression after transplant, so using high dose perioperative steroids as induction therapy to suppress this response is a good approach.
In Dizygotic twins are 2 times more than monozygotic twins
Usually have the same sex and same DNA testing by taking swab from inside the cheek, which is 100% accurate
Regarding immunosuppression :
Dizygotic twins will be managed as non twin siblings with low risk of rejection
but If they are 2 haplotype identical like our patient no antibody induction is recommend only corticosteroids
Maintenance therapy :
In white it is recommended to use triple therapy for first 3-6 m then shift to dual therapy with corticosteroid and antimetabolite (azathioprine or mycophenolate mophetil)
In African-American it is recommended to use triple therapy with corticosteroids, antimetabolite and low dose CNI (tacrolimus trough of 3-5 ng/ml or cyclosporine trough of 50-100 ng/ml)
In monozygotic twins some recommend no immunosuppression induction and give maintenance immunosuppression for 1-3 months
If dizygotic with 000 mismatch, no antibody induction is recommend only corticosteroids
Maintenance therapy differ in white vs African-American
⦁ In white it is recommended to use triple therapy for first 3-6 m then shift to dual therapy with corticosteroid and antimetabolite (azathioprine or mycophenolate mophetil)
⦁ In African-American it is recommended to use triple therapy with corticosteroids, antimetabolite and low dose CNI (tacrolimus trough of 3-5 ng/ml or cyclosporine trough of 50-100 ng/ml)
Monozygous twins come from a single fertilized ovum by one sperm, and studies have proved that monozygous twins are not genetically-related due to the mechanism of somatic variation, which can be caused by
A– Somatic mosaicism occurs in early embryo development and results in tissues having varying genetic expression like:
1- heteroplasmy (unequal division of mitochondrial DNA within the cellular cytoplasm)
2-uniparental disonomy (where both copies of a chromosome or genomic region are inherited from a single parent)
3- Chimerism occurs after introduction of external genetic element either from mother or inter-embryonic during pregnancy .
B- Epigenetic drift environmental alteration of the genetic content
So, regarding induction therapy in Tx :no randomized controlled trials valued using it . but still there are a few reports recommends that If you would chose off IS protocol better to be in carefully selected patients(,younger, White, and had a cold ischemia time of less than 12 hours).
In regards to rejection rates in identical twins , they noticed no significant risk of rejection between IS group and off IS group :however there were a noticeable diiference in the recurrence of the the 1 ry disease and side effect of IS .
.
DAMPs (damage-associated molecular patterns), among other chemokines, are released during ischemia-reperfusion injury and cellular stress during organ recovery which may modify gene expression after transplant, so using high dose perioperative steroids as induction therapy to suppress this response is a good approach.
to breif (in monozygotic twins if carefully selected young ,white ,less cold ischemia time ) no induction with or without maintainance steroid ) otherwise you can use induction with methylprednisolone and maint steroid.
In Dizygotic twins are 2 times more than monozygotic twins
Usually have the same sex and same DNA testing by taking swab from inside the cheek, which is 100% accurate
Regarding immunosuppression :
Dizygotic twins will be managed as non twin siblings with low risk of rejection
but If they are 2 haplotype identical like our patient no antibody induction is recommend only corticosteroids
Maintenance therapy :
In white it is recommended to use triple therapy for first 3-6 m then shift to dual therapy with corticosteroid and antimetabolite (azathioprine or mycophenolate mophetil)
In African-American it is recommended to use triple therapy with corticosteroids, antimetabolite and low dose CNI (tacrolimus trough of 3-5 ng/ml or cyclosporine trough of 50-100 ng/ml)
In monozygotic twins some recommend no immunosuppression induction and give maintenance immunosuppression for 1-3 months
If dizygotic with 000 mismatch, no antibody induction is recommend only corticosteroids
Maintenance therapy differ in white vs African-American
⦁ In white it is recommended to use triple therapy for first 3-6 m then shift to dual therapy with corticosteroid and antimetabolite (azathioprine or mycophenolate mophetil)
⦁ In African-American it is recommended to use triple therapy with corticosteroids, antimetabolite and low dose CNI (tacrolimus trough of 3-5 ng/ml or cyclosporine trough of 50-100 ng/ml)
It can be either monozygotic or dizygotic twin…so the differentiation between them is important because the recipient of a renal transplant from a monozygotic twin does not need immunosuppression. there are several methods used to determine identity eg, analysis of short tandem repeats(STR) and extended blood groups.
In dizygotic twins, immunosuppression is required.
VUR in twins , divided them into monozygotic and dizygotic pairs.
They found that a significantly greater number of monozygotic siblings (80%) had reflux when compared with the dizygotic group (35%).
If only the younger individuals in each group were considered, a group that had less time to experience spontaneous resolution of their reflux, then the difference in incidence increased even further to 100% for monozygotic and 50% for dizygotics.
This frequency strongly suggested an autosomal dominant mode of inheritance.
This means I need to check the donor first if she had VUR before donation, as the possibility of having the same disease of her sister is high.
Kaefer M, Curran M, Treves S et al (2000) Sibling vesicoureteral reflux in multiple gestation births. Pediatrics 105:800–804
1- If they are twins , they may be either monozygotic or dizygotic
As they are of the same sex and HLA mismatch is 000 so they are mostly monozygotic but further confirmation using genetic test and 13 or 17 Short Tandem Repeat sequencing is needed. In case of dizygotic twin , they may have the same sex in 50% of cases and share the same two haplotypes in 25 % of cases (Jorgensen D et al .,2020).
2- Regarding immunesuppression treatment
A- Step 1 : Immunological risk assessment through assessing HLA mismatch , cross match CDC and presence of DSA by PRA
Immunological of this patient is low as HLA mismatch is 000 , negative cross match and the cause of her ESRD isn’t GN , so is at low immunological risk .
B- Step 2 : confirm monozygosity
· Suggestive features of monozygozity : facial feature similarity , same ( sex , blood group ) and HLA mismatch is 000
· Definite diagnosis of monozycgosity is through genetic test using 13 or 17 short tandem repeat of certain DNA sequences .
In case of monozygotic twins and the cause of ESRD isn’t GN (as in this case):
· Induction therapy isn’t needed
· short and long term maintenance immune suppression may not be needed and if needed a small dose of steroid for short duration (up to 5 days) can be used. In their study, Jorgensen D et al found excellent short and long term graft survival in case of monozygotic twin transplantation where 50 % of included patients did not receive any immunesuppresion neither induction nor maintenance therapy and the major cause of graft failure was due to recurrence of GN after transplantation.
· In case of dizygotic twins: the immunological risk is still low so I would prefer to avoid induction therapy and follow a low steroid protocol and keep tacroulimus at a lower trough levels .
Ref
Jorgensen, Dana R., Christine M. Wu, and Sundaram Hariharan. “Epidemiology of end‐stage renal failure among twins and diagnosis, management, and current outcomes of kidney transplantation between identical twins.” American Journal of Transplantation 20.3 (2020): 761-768.
Twins either monozygotic or more common dizygotic to identify both types simple tests or factors are used such as sex,blood group and HLA match and confirmatory genetic test of zygocity using13 or 17 short tandem repeat (STR) also used to increase the certainty of the diagnosis.
Regarding immunosuppression:
Dizygotic twins need to be on low dose of immunosuppression but in monozygotic twins no need for immunosuppression unless it’s required in case of presence of other immunological diseases.
But long term follow up is mandatory for all aspect of renal function and renal biopsy should be done when indicated or worsening of renal function.
Is reflux nephrooathy in the case a hint to none immunological or non inflammtory Cause. Which favour IS free protocol. Reverse of some practice. who favour Immunosuppresion in CASES CAUED BY GN. Which carry more risk of recurence?!
Exciting clinical scenarios in the early course of the first module including HLA typing and matching .Although I was not actively involved in the donor- recipient selection during my nephrology fellowship, I tried to read more about immunology over the past two days in order to understand the question and try to answer correctly.
As mentioned earlier by many colleagues twins are not always identical. but identical twins share almost every single feature starting from the genes including those encoding the HLA antigens so they share phenotype and genotype and in this case twin to twin donation is associated with the better outcomes in kidney transplantation taking in consideration that the outcomes not only related to the lower or NO antigenicity but also less or no side effects from prescribed immunosuppression.
For the dizygotic twins or fraternal twins,that develop from separate fertilized ova, are genetically distinct and not necessarily of the same sex or same features. so in this case the antigenicity of the graft and immune response by the donor is determined by the hla matching or degree of mismatch.
in our case the mismatch 000and negative flow cytometry crossmatch is almost best match which implies that the patient is at lower risk for rejection and the decision for induction or maintenance immunosuppression should be taken in favor of minimal or no immunosuppression except for steroids in the early post-transplant course.
REGARDING THIS SCENARIO,WHICH IS UNCOMMON IN PARCTICE .I THINK DNA ANLYSIS WILL BE HELPFUL TO DISTINGUISH BETWEEN MONOZYGOTIC TWINS (WHICH CARRIES 100% OF THEIR GENETICS MATERIALS) AND THOSE DIZYGOTICS WHO SHARE ONLY 50% .
UPON DNA ANLYSIS, DESCION OF IMMUNSUPRRESION CAN BE MADE.
FOR MONOZYGOTIC TWINS , WE CAN GO WITH VERY LOW INDUCTION IMMUNSUPRREION LIKE METHYLPRED 500 MG INTRA OP JUST TO SUPREES CYTOKINE RELASE DUE TO IRI WHICH MAY ENHANCE AFTERWORDS IMMUNORESPONCE , AND NO NEED FOR MAINTINACE IMMUNSUPREESION.
REFERNCE
DOI:10.1016/J.NEFROE.2015.02.004
As mentioned by other colleagues it depends on type of genetics & whether they are identical twin or not . The data from Scientific Registry of Transplant recipients mentioned about 50% of identical twin recipients in USA are not on any immune suppressants drugs with same graft & patient survival comparing with patients on immune suppressants. after renal transplantation avoid both induction antibody & maintenance immune suppressant drugs in monozygotic renal transplant recipients unless needed to treat other immunological disease as SLE.
2 haplotype matched maternal twin may had minor histocompatibility antigen so they need immnosuppression.
References
Jorgensen D., Wu C., and Hariharan S. Epidemiology of end stage renal failure among twins and diagnosis, management, and current outcomes of kidney transplantation between identical twins. American Journal of Transplantation. 2019; (20):761-768.
In this case scenario the two sisters could be identical twin or not .
Dizygotic twins can be manged as any sibling and need to be maintained on immunosuppression but in case of monozygotic twin there are diffrent protocols
this must be confirmed by genitic testing of their DNA using PCR Based short tandem repeat analysis with other methods such as HLA typing and boold groups .
We have also to assess previous sensitization by pregnancy or blood transfusion.
The first kidney transplant between two identical twins, in 1956 doctors concluded that they were identical by performeing a full-thickness skin graft on the recipient and 31 days later a histological examination of the skin graft indicated no rejection and the graft survived 9 years without immunosuppression.
Monozygous twins come from a single ovum fertilized by one sperm, and recent studies have shown that monozygous twins are not genetically-related due to the phenomenon of somatic variation, which can arise from three different mechanisms: somatic mosaicism, chimerism and epigenetic drift.
DAMPs (damage-associated molecular patterns), among other chemokines, are released during ischemia-reperfusion injury and cellular stress during organ recovery which may modify gene expression after transplant, so using high dose perioperative steroids as induction therapy to suppress this response is a good approach. steroids may also be given for 5 to 7 days following transplantation.
Almost half of transplanted identical twins had immunosuppression for at least a year as
Most of doctors find discomfort to leave the patient’s without immunosuppression especially if the original cause of renal failure was glomerulonephritis which is not the case in this scenario despite the studies that showed no difference in survival of patients or graft at 6 months,1 and 5 years between groups who received immunosuppression and who didn’t .
Putting into consideration the risk of increasing infections and malignancy
And other complications of immunosuppression drugs as diabetes ,Hypertension and osteoporosis i would go for short term dual immunosuppression for 3-6 months and close monitoring if graft function and rena biopsy if needed
They can be either monozygotic or dizygotic twin
Kidney transplantation from a monozygotic twin living donor is associated with excellent clinical outcomes. Immunosuppressive therapy to suppress alloimmune response is probably unnecessary if zygosity has been confirmed
They could be either monozygotic or dizygotic
Monozygotic twins came from single ovum fertilised by single sperm , that is them undergo division
Siblings have the same sex and genetic material and there is always 100%HLA match , and not necessarily phenotypicaly identical
Dizygotic twins came from fertilisation of 2 ova by 2 sperms in the same pregnancy ,
Siblings have half of the genetic material same as other Siblings came from different pregnancies ,
And there is a small chance of having 100% match in their HLA
the most important issue when transplantation is planned , is to confirm the donor and potential recipient are identicle twins
This should be done initially by confirming that date of birth, sex, blood type, and HLA A, B, and DR antigens are the same.
However, as a final step to confirm the donor/recipients’ monozygotic status prior to transplantation using either 13 or 17 short tandem repeat (STR) tests for select regions on the DNA.
Panel reactive antibody screening for Class I and II antigens, as well as T- and B-cell crossmatch tests also need to be done between donor and recipient.
After transplantation of confirmed identical twins , physicians should avoid both induction antibody treatment as well as maintenance immunosuppression , unless treatment is required for other cause
steroids may be given for 5 to 7 days during early postoperative inflammatory state ,
Whether to further withdraw rest of immunosuppression or not , should be individualized
It looks; There’s no agreement regarding twin transplant immunosuppression, giving the low risk of rejection. The large study done by identical twins in 2001-2017, lead author Dana Jorgensen, PhD, MPH, an epidemiologist at the University of
Pittsburgh Medical Center(1), shows no difference in outcome between those who’s on and those who’s not on immunosuppression.
A short Course i.e. A week of glucocorticoid is acceptable.
Important issue is confirm that twin are identical before transplant, as most monozygotic are not genetically so, due to what’s called somatic variation(2) …So short tandems sequence PCR should be done.
Those identical transplanted should be followed posttransplant for evidence of develop of immunity or rejection ,by sequence.Biopsy,PRa,RFT AND immunosuppression given as indicated.
Reverse for dizygotic twin where all typing and cross march should be done.
Reference:
1.Dana.R.Jargoson etal ,Epidemiology of end-stage renal failure among twins and diagnosis, management, and current outcomes of kidney transplantation between identical twins,American journal of transplantion.vou.20 ,issue 3 .March 2020.2.Elizabith ,Day ,Transplantation Between Monozygotic TwinsHow Identical Are They?
Transplantation: September 15, 2014 – Volume 98 – Issue 5 – p 485-489.
Twins can be either dizygotic or monozygotic (or identical).
Monozygosity between a donor-recipient pair can be confirmed by concordance in sex, blood type, and HLA antigen match
Dizygotic twins do not have identical DNA but instead share roughly 50% of their DNA with siblings
Diagnosing zygosity has important implications for transplantation and immunosuppression management
Renal transplantation between monozygotic identical twins provides an opportunity to utilize minimal immunosuppression to maintain stable allograft function.
However, recurrence of GN is an important issue affecting graft survival between monozygotic twins
VUR occurred in 1-2% of pediatrics.
VUR is genetically heterogeneous
The siblings of child with VUR has increased incidence to have VUR more than general pediatrics
Twin could be monozygotic (identical) or dizygotic, no accurate method can determine monozygotic twin, there are several methods like DNA and finger print but has limitations.
There is controversy in the safety of immunosuppression withdrawal and minimization of medications , because there are many factors which may lead antibody activation or T cell activation like original disease, history of blood transfusions and others
references:
Prem Puri 1, Jan-Hendrik Gosemann, John Darlow, David E Barton Genetics of vesicoureteral reflux. Nat Rev Urol. 2011 Aug 23;8(10):539-52.
Idris Yakubu, 1 Abdolreza Haririan, 2 Stephen Bartlett, 2 and Tracy Sparkes 1 Successful Renal Transplantation between Identical Twins with Very Brief Immunosuppression. Case Rep Transplant. 2018; 2018: 9842893.
Dear All
Excellent contributions, but I have noticed copying and pasting for articles. My sincere advice to you is to read the article, write the answer in your own words. This will make you remember the answer for a long time. It is also a practice for the assignments
a brief course of steroids, a calcineurin inhibitor and an antimetabolite in monozygotic twin recipient(6 months). then continue on (CNI+STEROID). The reason for this is that the mechanism of rejection of an allograft is not solely based on alloantigen recognition, but also on other factors that increase immune response and therefore, the risk of rejection. Trauma and ischemic damage to the tissues during surgery release cytokines and other endogenous “alarm or danger signals” that can activate the immune cascade despite complete HLA homology between the donor and recipient.
In addition, oxidative and ischemia-reperfusion injury associated with the surgery may modify donor DNA and has the potential to alter gene expression post-transplantation. These “epigenetic modifications” can predispose to allograft rejection.
Since 25%of dizygotic twins are zero mismatched we can’t make sure whether they are monozygotic. To confirm their monozygosity, genetic test such as short tandem repeat (STR) sequencing should be done. If allelic identity is shown, then they are considered monozygotic twins. Immunosuppression in this condition can be minimized but there are some controversies. If the primary disease that caused ESKD is not immunologic such as reflux nephropathy in this case, no induction therapy except methylprednisolone is needed and maintenance immunosuppression can be minimized and then stopped.
References:
1. Jorgensen, DR, Wu, CM, Hariharan, S. Epidemiology of end-stage renal failure among twins and diagnosis, management, and current outcomes of kidney transplantation between identical twins. Am J Transplant. 2020; 20: 761– 768.
2. Yakubu I., Haririan A., Bartlett S., Sparkes T. Successful Renal Transplantation Between Identical Twins With Very Brief Immunosuppression. Case Rep Transplant. 2018; 2018: 9842893.
First we should confirm the zygosity as mentioned above by means of a reliable methods.
If monozygotic there is a possibility of discordant protein presentation in identical twins that could trigger alloimmune response and lead to graft injury. The immunosuppressant withdrawal or minimization in this group of people need to be individualized and we must also consider some risk factors like the likelihood of primary disease recurrence . So there is recommendations to the use of steroids perioperatively to prevent rejection resulting from activation of innate immune response due to ischemic reperfusion injury, along with close posttransplant monitoring. Isograft
Isografts are allografts in which organs or tissues are transplanted from a donor to a genetically identical recipient (e.g. an identical twin). Therefore, the optimal immunosuppression regimen in this patient population is unknown, and the safety of immunosuppression withdrawal remains controversial.
If they are dizygotic …they are different in non HLA and minor antigens so….risk assessment should be done and risk categorization of our patient then decide the best plan over individualized decision.
Reference:
Successful Renal Transplantation between Identical Twins with Very Brief Immunosuppression. Case Report | Open Access
Volume 2018 |Article ID 9842893 | https://doi.org/10.1155/2018/9842893.