|Year : 2020 | Volume
| Issue : 1 | Page : 5-7
Thrombotic microangiopathy and rejection in blood group incompatible renal transplantation
Praveen Kumar Etta
Department of Nephrology and Renal Transplantation, Max Superspeciality Medical Centre, Virinchi Hospitals, Hyderabad, Telangana, India
|Date of Submission||01-Dec-2019|
|Date of Acceptance||23-Feb-2020|
|Date of Web Publication||31-Mar-2020|
Dr. Praveen Kumar Etta
Department of Nephrology and Renal Transplantation, Max Superspeciality Medical Centre, Virinchi Hospitals, Hyderabad, Telangana
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Etta PK. Thrombotic microangiopathy and rejection in blood group incompatible renal transplantation. Indian J Transplant 2020;14:5-7
The ABO blood group antigen system consists of oligosaccharides that are not only expressed on red blood cells (RBCs), but also on various tissues and cells including lymphocytes, platelets, epithelial, and endothelial cells (renal tubular and glomerular cells) making the ABO antigen system important for kidney transplantation (KT). The blood group antibodies (anti-A/B antibodies) are formed against those antigens that are not native to the host, on contact with gut bacteria during early infancy (e.g. “A“ blood group person has “A“ antigen on the surface of RBCs and anti-B antibodies in serum). Naturally occurring anti-A/B antibodies are predominantly of the immunoglobulin (Ig) M class but in blood group “O“ individuals IgG and IgA class antibodies are also present. Hence, ABO compatibility was essentially required in organ transplantation till the recent past. With the current availability of various desensitization therapies, ABO incompatible (ABOi) transplantation became possible with good graft and patient survival rates. The aim of desensitization therapies is to reduce the level of circulating preformed anti-donor antibody titers to a safe threshold level as higher titers are associated with antibody mediated rejection (ABMR) posttransplant. Patients with different blood groups differ with respect to their antigen density on RBCs. Blood group “A“ consists of two subtypes, A1 and A2. A1 being more prevalent, but the antigenic expression of A2 is quantitatively and qualitatively less than that of A1. The order of antigen expression and immunogenic risk is A1 > B > A2. Given the lower immunogenicity of organs from blood group A2 donors, donor A2 kidneys can generally be successfully transplanted into recipients with low pretransplant anti-A antibody titers without the need of desensitization. Blood group “O“ individuals tend to have higher isoagglutinin antibody titers (anti-A and anti-B) as compared to blood group “A“ and “B“ individuals, and they also have a higher frequency of IgG antibodies. Hence, blood type “O“ recipients have a higher incidence of rejection following ABOi transplantation.
Thrombotic microangiopathy (TMA) following KT is a devastating complication that is associated with poor patient and graft outcomes. It can occur either as de novo (developed for the first time without any evidence of the disease before transplant) or recurrent form (native kidneys failed as a result of TMA, and it recurred after KT). De novo TMA constitutes the vast majority of post-KT TMA cases and is caused by a heterogeneous set of various etiologies such as ABMR, drug toxicity (calcineurin inhibitors [CNIs], mammalian target of rapamycin inhibitors, anti-vascular endothelial growth factor therapies, etc.,), or viral infections (hepatitis C, cytomegalovirus, BK, and parvovirus). Most cases of recurrent TMA result from underlying complement dysregulation with alternative pathway overactivity with a history of atypical hemolytic uremic syndrome in native kidneys affected with end-stage renal disease. Few cases of recurrent TMA are misclassified as de novo type as renal biopsy of native kidneys is not performed in many patients due to several reasons including terminal presentation; hence, missed diagnosis of TMA prior to KT is likely. The recurrent TMA can also be triggered by anti-human leucocyte antigen (HLA) antibodies, viral infection, ischemia-reperfusion injury, and immunosuppressive medications which can initiate the cascade of complement activation in susceptible patients. Distinguishing de novo and recurrent TMA will invariably have clear clinical and therapeutic implications. In contrast to systemic TMA affecting native kidneys, renal limited TMA without any systemic features is quite common in transplant setting and is identified only on allograft biopsies. The majority of these renal limited TMAs occur due to either drug toxicity (especially CNIs) or ABMR. In contrast to de novo TMA, recurrent TMA almost always presents as systemic form of TMA. TMA in deceased donor transplantation is more prevalent; ischemia reperfusion injury thought to play a major role leading to endothelial injury and consequent TMA. ABOi transplantation may itself is a risk factor for TMA in both kidney and liver transplantation., TMA in these cases of ABOi KT can be a manifestation or complication of ABMR especially in the presence of significant level of anti-donor antibodies. A recent large retrospective study that included 1485 living KTs with 406 ABOi transplantations showed that the prevalence of TMA was significantly high in the ABOi cases with hazard ratio of 2.89 compared to ABO compatible cases and TMA developed within 90 days after KT in all the cases. They concluded that ABOi KT itself is a significant risk factor for TMA. There is scarcity of Indian data on TMA in ABOi KT. In an Indian study that included 20 ABOi KTs, only one got affected with TMA.
ABMR is the primary cause of graft loss in ABOi KT. Hyperacute rejection occurs immediately (within few hours to days) after transplantation. It is mediated by high titer of preformed anti-donor antibodies: Anti-HLA, anti-ABO, or other non-HLA antibodies. It results in an irreversible vascular rejection, intravascular thrombosis, and graft necrosis; and graft nephrectomy is usually indicated. The availability of pretransplant crossmatch techniques and the use of ABO compatible donors essentially eliminated hyperacute rejection. Following desensitization, the rejection in ABOi KTs does not usually occur within 24 h, which is called the silent period. The greatest incidence of acute ABMR occurs 2–7 days after transplant ( first 2 weeks period is considered as the critical period). It does not typically occur after more than 1 month after ABOi KT due to the development of “accommodation“ which is the resistance of allograft to ABMR despite the significant presence of anti-ABO antibodies in the recipient serum (stable period). Unintentional blood group mismatch KT can cause detrimental hyperacute rejection. It is recommended to perform both cell typing and serum typing to identify rare blood groups such as Bombay blood group and para-Bombay blood group. Similar to “O“ group, Bombay group individuals have anti-A and anti-B antibodies in serum, with no A/B antigens expressed on RBC surface; the specific feature is that anchoring antigen “H“ is also absent on the surface of RBC and their serum contains anti “H“ antibodies. Hence, they can be considered as universal donors in organ transplantation, but it can lead to hyperacute rejection if they receive organ from any blood group individual without desensitization. The AB para-Bombay blood type is characterized by expression of blood group “A“ and “B“ antigens on tissues (including kidney) but not on RBC; serum contains anti-H antibodies but not anti-A or anti-B antibodies. In them during ABO typing, discordant results are noted on the cell typing and serum typing, identified as “O“ group on cell typing and “AB“ on serum typing. Due to the expression of blood group antigens in renal tissue, KT from these donors to non-AB blood type recipients is considered to be ABOi KT, though RBC does not express any blood group antigens on their surface. Hence, blood type evaluation for transplantation should include antigen as well as antibody detections, including “H“ antigen and anti-H antibody. KT from these rare blood group donors has been reported in the literature., The definite role for the Lewis blood group antigen system in KT rejection is not yet established. Lewis antigens are expressed on cell surfaces of the renal parenchyma in Lewis-positive persons. Lewis antigen system could be the source of diminished allograft survival in recipients who are mismatched with their organ donors for Lewis antigens. However, the absence of hyperacute rejection phenomena in Lewis-incompatible grafts may be due to the lack of Lewis antigens on endothelial cell membranes, which are the targets of hyperacute rejection. Lewis antigens may be capable of inciting both cell-mediated and humoral immune responses of a cytotoxic nature; hence, Lewis incompatibilities between kidney donors and recipients may contribute to allograft rejection.
In a case reported in earlier issue, the authors have identified severe acute TMA mimicking a hyperacute rejection like episode in an ABOi KT which required graft nephrectomy at 3 months after transplantation. They proposed that TMA could be due to interaction between endothelial cells of renal allograft and anti-donor hemagglutinin antibodies. They concluded that anti-donor hemagglutinin antibodies even in low titers can still be pathogenic and contribute to allograft TMA leading to graft loss even in the absence of complement activation; whether such severe TMA mimicking hyperacute rejection in these cases of ABOi KT occurs as a manifestation of ABMR induced by anti-donor hemagglutinin antibodies even in very low titers requires further study.
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