The Role of CTLA4 and Its Polymorphisms in Solid Organ and Haematopoietic Stem Cell Transplantation

HLA matching, transplantation technique, or underlying disease greatly influences the probability of long-term transplantation success. It has been hypothesised that genetic variation affecting antigen presentation also contributes to the outcomes of both solid organ transplantation and allogeneic haematopoietic stem cell transplantation (AHSCT). Those genes, along with those responsible for innate and adaptive immunity, have become targets of investigation. In this review, we focus on the role of CTLA4 in the process of acute graft rejection and summarise the progress in our understanding of its role in predicting the outcome. We present the results of the latest studies investigating the link between CTLA4 gene variability and AHSCT, as well as organ transplantation outcomes. While some studies found a link between +49 A/G and -318 C/T and transplantation outcomes, comprehensive meta-analyses have failed to present any association. The most recent field reviews suggest that the -1772 T/C (rs733618) CC genotype is weakly associated with a lower risk of acute graft rejection, while +49 A/G might be clinically meaningful when investigated in the context of combinations with other polymorphisms. Studies verifying associations between 12 CTLA4 gene SNPs and AHSCT outcomes present inexplicit results. Some of the most commonly studied polymorphisms in this context include +49 A/G (rs231775) and CT60 A/G (rs3087243). The results signify that, in order to understand the role of CTLA4 and its gene polymorphisms in transplantology, further studies must be conducted.

BK polyomavirus genotypes and progression of BKV disease in renal transplant recipients

Background. BK virus (BKV) reactivation is a significant cause of BK Polyomavirus associated nephropathy (BKPyVN) resulting in acute graft rejection in 1-10% of post-renal transplant recipients. However, the association of BKV genotypes with development of BKPyVN is poorly understood. Here we aimed to determine the prevalence of BKV genotypes in post-renal transplant recipients, and its association with BKPyVN disease progression. Method. Two methods were utilised to genotype BKV. A 800bp fragment of virus VP1 antigen region was amplified using nested (PCR) followed by sequencing. The genotypes were determined according to a previously developed algorithm based on analysing 100bp region of the VP1 gene. Furthermore, the logarithm results were validated with the constructed phylogenetic tree. The results were correlated with patient viral loads and development of BKPyVN. Results. BK virus DNA was detected in 32 (69%) of 46 post-renal transplant recipients with BK viremia, while BKPyVN was only reported in two (4.3%)patients. 30 out of 32 samples were successfully genotyped (93.7%) with 23 (76.6%) belonging to the BKV Ib-2 subtype and seven (23.3%) belonging to the BKV Ib-1 subtype and with no cases representing genotype II, III and IV. All cases with confirmed BKPyVN matched to the BKV Ib-2 genotype. Additionally, no significance differences were observed between BKV genotypes in regards to viral loads, development of viremia, HLA mismatch, age or sex. Conclusion. The results indicate no correlations between BKV genotypes and the development of BKPyVN. Furthermore,a high distribution of BKV genotype Ib-2 was found among BKV infected patients within this cohort.

Early Acute Graft Rejection in a Heart Transplanted Child with Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is the most common type of cardiomyopathy in children. Heart transplantation is considered standard therapy in dilated cardiomyopathy with end-stage heart failure. We present a case of a 15-year-old patient diagnosed with DCM in the neonatal period, who underwent heart transplantation for end-stage heart failure. Despite the use of induction therapy, the endomyocardial biopsy performed at two weeks post-transplant revealed mixed moderate cellular (2R) and humoral (pAMR2) allograft rejection. Aggressive rejection treatment was initiated with good outcome. Besides endomyocardial biopsy, advanced echocardiography can also be a valuable noninvasive tool for rejection assessment.

NUMBER NEEDED TO TREAT AS A TOOL FOR COST EFFECTIVENESS ANALYSIS: A CASE STUDY IN RENAL TRANSPLANTATION

Objective: To assess the utility of number needed to treat (NNT) as a tool for cost effectiveness analysis. Methods: Two monoclonal antibodies (MAbs), used for induction therapy viz basiliximab and daclizumab in renal transplantation, were identified. Pivotal placebo controlled clinical trials, mentioned in the innovator package inserts, were compared and analyzed for acute graft rejection and graft survival at 12 mo. NNT viz-a-vis cost was calculated and compared. Results: Daclizumab was comparable to basiliximab for acute graft rejection (NNT 10 vs. 9) but better for graft survival (20 vs. 25) at 12 mo, when used along with triple drug regimen (cyclosporine, azathioprine and corticosteroid). However, considering the cost of regimen for these drugs, in terms of NNT, basiliximab was more cost effective (INR 12,52,044 vs. 28,70,400 for acute rejection and INR 34,77,900 vs. 57,40,800 for graft survival). On the other hand, when these MAbs were used along with dual drug regimen (cyclosporine and corticosteroid), daclizumab was more cost effective for graft survival at 12 mo. The higher cost of daclizumab regimen (INR 2,87,040 vs. 1,39,116 for basiliximab) was offset by its substantially lower NNT (20 vs. 58-75 for one extra graft survival at 12 mo). Conclusion: This study demonstrates the utility of NNT in ascertaining relative effectiveness of treatment modalities that would help to formulate appropriate healthcare policies.