Kidney Transplantation in Identical Twins: Do They Need Immunosuppresion?

The first kidney transplant between two identical twins, the Merrick brothers, took place on Dec 23, 1956 in Boston, MA and its is very interesting to read the original article and how Dr. Merril and Dr. Murray concluded that they were identical. They performed a full-thickness skin graft on the recipient and 31 days later a histological examination of the skin graft indicated no rejection and these observations among other clinical findings lead the investigators to conclude that they were monozygous twins and rejection would be unlikely. No HLA typing existed at that time. Surgery was successful and Mr. Herrick lived for 9 years after the transplant without receiving any maintenance immunosuppression. He later died secondary to a myocardial infarction. The side effects of immunosuppression (IS) is a constant battle for nephrologists and finding a sweet spot on maintaining adequate IS to prolong graft survival and avoiding side effects is almost impossible to achieve.

A few days ago we took care of a 72 year-old female that underwent living donor kidney transplantation from her identical twin. Prior to surgery there was a discussion whether the recipient should get any induction and maintenance IS. She was a 0/6 HLA mismatch and genetic testing using PCR-based Short Tandem Repeats (STR) analysis indicated they were identical for the 16 different polymorphic gene loci that were evaluated and because she was elderly and highly functional she was at a low immunological risk. 

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. Somatic mosaicism occurs in early embryo development and results in tissues having varying genetic expression arising from a single zygote (think about the Rubik’s cube) 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 arises when new genetic material is introduced from an exogenous source such as maternal cells entering fetal circulation or between two embryos in multiple pregnancies. Epigenetic drift is the result of genetic alterations that have been accumulated throughout life as a result of the interaction of genes and environment (early in utero and lifestyle).

So, should monozygous twins receive any induction or maintenance IS? First of all, there are no randomized controlled trials addressing this question and there have been only a few reports where patients received minimal or no immunosuppression. In this article, the authors reported 194 probable identical twin transplants. Seventy percent of the cases received steroids as induction and 71% were discharged with some form of IS therapy. At one year post-transplant, 21% of recipients were receiving calcineurin inhibitors and 27% were on steroids. By one year post-transplant, 66% percent of recipients were not on any form of IS. Recipients off IS, tended to be 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, the authors reported 120 cases in the US and 12 cases in the UK and they concluded that there was no significant difference in graft survival between recipients that are received IS and those who did not. In addition, they also reported no differences on cases that had maintenance IS for possible recurrence disease in comparison to those recipients at low risk for recurrence disease. In another series of 5 cases in a single center between 1969 and 2013 in Spain of kidney transplantation between monozygotic twins, the investigators reported good outcomes at one and five years. Recipients received only a single dose of high dose steroids intraoperatively and no maintenance IS. Of this five cases, two recipients died (from cardiovascular disease and melanoma) after 16 and 22.5 years post-transplant, respectively. One patient was lost to follow up and the two remaining were still alive.

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. The somatic variation phenomena described in monozygotic twins should also be considered since they are not strictly identical. In conclusion, once the immune system has been adequately suppressed after the initial inflammatory response related to kidney transplantation surgery, the next step would be to attempt reducing or withdrawing maintenance IS very cautiously considering postoperative course, primary disease and pathological graft findings. Our patient received only high dose steroids as induction IS.

Image from Bioinfoworld

If ANCA cause vasculitis, what causes ANCA?

Over the past decade, controversy about whether ANCA is itself directly pathogenic has largely abated, primarily based on convincing animal models of small vessel vasculitis in mice and rats mediated by MPO ANCA. But as this issue is laid to rest, a new burning question has emerged in the field: if ANCA cause disease, what causes ANCA? Specifically, why are the ANCA antigens PR3 and MPO turned on in the neutrophils of ANCA patients, and not in their normally silenced state (as in healthy controls). This question hints at the regulation of gene expression itself, and brings us to the rapidly expanding field of epigenetics.

Epigenetics, the study of changes in phenotype and/or gene expression that are independent of the underlying DNA sequence, is one of the hottest areas of basic science research at the moment. Recently, the Jennette and Falk group in Chapel Hill examined whether high expression of the major auto antigens in ANCA patients, MPO and PR3, might have an epigenetic basis. The reason this is a good bet is that, although mature neutrophils from healthy subjects do not express MPO and PR3, these proteins are expressed in developing neutrophils. This suggests that there is transcriptional silencing of MPO and PR3 during development, which is the hallmark of epigenetic control.

They showed that levels of a specific histone methylation (H3K27me3) were reduced at the MPO and PR3 loci in ANCA neutrophils compared to those from healthy controls. H3K27me3 is associated with the formation of heterochromatin, which is inaccessible to transcription and often causes gene silencing. They went on to show that Jmjd3, the demethylase responsible for removing this particular histone methylation is upregulated in ANCA patients. This suggests that Jmjd3-mediated changes in histone methylation status may be responsible for aberrant expression of MPO and PR3 in mature ANCA neutrophils. This study throws up a number of areas for further research. For example, elucidation of what causes the initial failure of gene silencing mechanisms will give further insight into the pathogenesis of the disease, whilst insight into the pathways which both establish and maintain silence of MPO and PR3 in healthy patients may suggest new therapeutic approaches.

Thomas Oates MD