Outcomes and Allograft Survival of Patients Who Underwent a Second Kidney Transplant and Were Followed Up for 10 Years.

BACKGROUND: Kidney transplantation is the treatment of choice for end-stage kidney disease, and a second transplantation becomes an opportunity for a better chance for long-term survival and quality of life. This study aimed to evaluate the outcomes and graft survival of patients transplanted a second time in comparison with single kidney transplant patients. METHODS: This retrospective observational study was conducted using a cohort of kidney transplant patients from 2008 to 2018. Fifty patients who underwent first transplant were randomly selected as group 1 (G1), and 31 patients who received a second kidney transplant as group 2 (G2). Outcomes, graft, and patient survival were assessed. RESULTS: G2 patients had higher proportions of rejection episodes and graft loss than G1. Fifteen (48.39%) patients from G2 maintained functioning grafts during follow-up, while 16 (51.61%) lost their grafts. The 10-year graft survival rate for patients with first transplant was 76.66%; it was 46.09% for retransplanted patients (P = 0.005). There was no statistically significant difference in patient survival between G1 and G2. CONCLUSIONS: Allograft survival rates of the first and second transplant with living donors had no statistically significant difference, but for deceased donors, poor graft survival was observed for the second allograft.

Clinical Outcome of Kidney Transplant Patients on the Allograft Function, Loss, Effects of HLA-DQB1-DSA+, and Graft Survival.

INTRODUCTION: Matching for HLA-DQB1 molecules and anti-DQ donor-specific antibodies (DSAs) has been less studied to allocate transplants from deceased donors in developed countries. The aim of this study was to evaluate the clinical outcome of 519 kidney transplant recipients on the allograft function, loss, and survival and with emphasis on effects of HLA-DQB1-DSA+ at minimum of 10 years' follow-up. METHODS: Five hundred nineteen kidney transplant patients were allocated into 3 groups (G) by immunologic profiles, namely, G1 (SPI-SAB HLA-DQ negative [DQ-]), G2 (SPI-SAB HLA-DQ positive DSA negative [DQ+/DSA-]), and G3 (SPI-SAB HLA-DQ DSA positive [DQ+ DSA+]), and the outcomes were reported until 10 years after transplantation. RESULTS: The proportion of rejection episodes was higher in G3 (25.0% and 26.32%, respectively) than in G1 (8.63% and 6.82%, respectively) and G2 (10.0% and 0%, respectively; P = .047 and P = .014, respectively). In G3, 3 patients lost their grafts by antibody-mediated rejection. Patients who received kidneys from deceased donors (G3) showed worse graft survival rates than those from G1 donors (P = .001). Patients from G3 had a 2.18-fold higher risk of graft loss than patients from G1 (P = .028). CONCLUSION: Allograft function was worse in G3 than in G2 or G1, and graft losses were more frequent by T-cell-mediated rejection in G1, and graft losses by antibody-mediated rejection were similar in G1 and G3 due to HLA class I (A1, 11 and B 8, 52) and HLA class II by DR7 and DQ 2, 5, 9 DSA, respectively. Allograft survival decreased in patients with HLA-DQB1 DSA. The risk of graft loss was 1.75-fold that in patients who received transplants from living donors.

An open-label randomized clinical trial to evaluate the efficacy of everolimus versus tacrolimus in triple maintenance immunosuppressive therapy for kidney transplant patients.

Tacrolimus (TAC), a calcineurin inhibitor, and everolimus (EVL), an mTOR inhibitor, have been used as immunosuppressive (ISS) drugs in post-kidney transplantation therapy. The objective of this study was to compare the efficacy of EVL vs TAC in the ISS maintenance triple therapy. Ninety-seven kidney transplant patients, who received triple maintenance therapy with TAC, mycophenolate mofetil (MMF), and methyl prednisone (PRED), were evaluated. After four months of post-kidney transplant therapy, 30 patients enrolled in a randomized controlled clinical trial, in which 16 patients received TAC+MMF+PRED (cohort 1), and 14 patients switched to EVL+MMF+PRED (cohort 2). The patients were followed-up for 36 months. Two patients from cohort 1 lost their grafts after one year due to non-adherence. Two patients from cohort 2 had intolerance to mTOR inhibitors and were switched back to TAC from EVL. One case (6.25%) in cohort 1 and three cases (21.43%) in cohort 2 of acute T-cell-mediated rejection was observed. Antibody-mediated acute rejection (ABMAR) was observed in four patients (25.0%) in cohort 1, and antibody-mediated chronic rejection (ABMCR) was observed in two patients (12.50%). One patient from cohort 2 lost the graft after 15 months due to polyomavirus infection. The graft survival rate was 87.50% in cohort 1 and 92.86% in cohort 2. This clinical trial showed that the EVL+MMF+PRED triple maintenance therapy was efficacious compared with TAC during 32 months of follow-up. However, further studies are needed to confirm the efficacy of this regimen for long-term graft survival.

An open-label randomized clinical trial to evaluate the efficacy of everolimus versus tacrolimus in triple maintenance immunosuppressive therapy for kidney transplant patients

Tacrolimus (TAC), a calcineurin inhibitor, and everolimus (EVL), an mTOR inhibitor, have been used as immunosuppressive (ISS) drugs in post-kidney transplantation therapy. The objective of this study was to compare the efficacy of EVL vs TAC in the ISS maintenance triple therapy. Ninety-seven kidney transplant patients, who received triple maintenance therapy with TAC, mycophenolate mofetil (MMF), and methyl prednisone (PRED), were evaluated. After four months of post-kidney transplant therapy, 30 patients enrolled in a randomized controlled clinical trial, in which 16 patients received TAC+MMF+PRED (cohort 1), and 14 patients switched to EVL+MMF+PRED (cohort 2). The patients were followed-up for 36 months. Two patients from cohort 1 lost their grafts after one year due to non-adherence. Two patients from cohort 2 had intolerance to mTOR inhibitors and were switched back to TAC from EVL. One case (6.25%) in cohort 1 and three cases (21.43%) in cohort 2 of acute T-cell-mediated rejection was observed. Antibody-mediated acute rejection (ABMAR) was observed in four patients (25.0%) in cohort 1, and antibody-mediated chronic rejection (ABMCR) was observed in two patients (12.50%). One patient from cohort 2 lost the graft after 15 months due to polyomavirus infection. The graft survival rate was 87.50% in cohort 1 and 92.86% in cohort 2. This clinical trial showed that the EVL+MMF+PRED triple maintenance therapy was efficacious compared with TAC during 32 months of follow-up. However, further studies are needed to confirm the efficacy of this regimen for long-term graft survival.

Six novel HLA-B, -DRB1, and -DQB1 alleles identified in Brazilian individuals.

The novel HLA alleles B*40:331, B*40:343, B*42:24, DRB1*01:74, DQB1*03:243, and DQB1*03:02:20 were identified in Brazilian individuals.

Delayed Graft Function, Predictive Factors, and 7-Year Outcome of Deceased Donor Kidney Transplant Recipients With Different Immunologic Profiles.

BACKGROUND: Delayed graft function (DGF) is the major post-transplant cause of deleterious effects to the allograft and is associated with poor allograft survival. The aim of this study was to report the outcomes of 236 kidney transplant recipients with different immunologic profiles. METHODS: All patients underwent transplantation (2008-2016) with a deceased donor at the University Hospital of the Faculty of Medical Science, Belo Horizonte, Minas Gerais, Brazil. Patients were classified into 3 groups according to immunologic profiles: nonsensitized (NS), sensitized without donor-specific antibody (SDSA-), or sensitized with donor-specific antibody (SDSA+). RESULTS: DGF was observed in 128 (54.24%), including 63 (49.22%) NS, 51 (39.84%) SDSA-, and 14 (10.94%) SDSA+ patients. The development of DGF was associated with dialysis for ≥49.25 months (odds ratio [OR] 2.30), donor age ≥42.25 years (OR 1.77), donor end creatinine level >1.22 mg/dL (OR 1.94), and cold ischemia time >12 hours (OR 2.45). Of the 55 patients with rejections, 37 (15.68%) had T-cell-mediated rejection (TCMR) and 18 (7.63%) had antibody-mediated rejection (AMR). Nine patients (16.36%) exhibited graft loss, 2 (0.85%) via TCMR in the SDSA- DGF+ group and 7 (2.97%) via AMR, including 2 NS DGF-, 2 SDSA- DGF-, 1 SDSA- DGF+, and 2 SDSA+ DGF+ patients. Graft survival significantly differed between the NSDGF- and SDSA- DGF+ groups (P = .014) and between the NS DGF- and SDSA+ DGF- groups (P = .036). CONCLUSION: In the 7-year period following transplantation, TCMR was more prevalent than AMR among patients with DGF. Graft loss was less prevalent among patients with TCMR than among those with AMR.

Genetic Mechanisms Involved in the Generation of HLA Alleles in Brazilians: Description and Comparison of HLA Alleles.

BACKGROUND: The HLA genes show high levels of diversity as indicated by the number of HLA alleles. There are almost 11,000 classical HLA-A, -B, -DRB1 alleles in populations around the world, making the search for compatible donors difficult. HLA diversity is generated by different genetic mechanisms, such as point mutations, which result in single nucleotide polymorphisms, insertion and deletion, and recombination. The aim of this study was to describe genetic mechanisms involved in the generation of HLA alleles in Brazilians. METHODS: Twenty-six alleles indentified in the Brazilian bone marrow donors were include in the study. Data regarding new HLA alleles by sequence-based typing were also used to elucidate what genetics mechanism was involved in the HLA variability. The new alleles were officially named by the World Health Organization Nomenclature Committee. RESULTS: The new alleles described were HLA-DRB1*11:04:14, HLA-A*33:117, and HLA-B*41:48. The DRB1*11:04:14 allele was generated by synonymous point mutation at codon 48. The A*33:117 allele was generated by nonsynonymous nucleotide mutation leading to amino acid substitution at codon 74. The B*41:48 allele was generated by an intralocus gene conversion between the HLA alleles from groups HLA-B*13, B*35, B*53, or B*58 and an allele from the HLA-B*41 group. CONCLUSIONS: Different genetic mechanisms introduce new mutant HLA alleles into the human population requiring attentive and rigorous specialists and the use of different methodologies to identify these mutations in HLA typing routine.

Identification of the novel allele, HLA-B*14:56, in a Brazilian individual.

Novel allele, HLA-B*14:56, generated by a gene conversion event was identified in a Brazilian individual.

A novel allele, HLA-B*51:220, identified in an individual from south of Brazil.

Novel allele, HLA-B*51:220 generated by a gene conversion event was identified in a Brazilian individual.

Two novel alleles, HLA-A*02:643N and HLA-B*53:44, identified in Brazilian individuals.

Two novel alleles, HLA-A*02:643N and HLA-B*53:44, generated by different mechanisms, were identified in Brazilian individuals.

A novel HLA allele, HLA-B*50:48, identified by sequencing-based typing.

The HLA-B*50:48 allele differs from HLA-B*50:01:01 by one nucleotide substitution at position 130.

Kidney Transplantation With Ultralong-Term (42 Years) Survival of a 100-Year-Old Graft.

BACKGROUND: In kidney transplantation, long-term graft survival has improved over the last few decades. Study to understand ultralong-term graft survival with graft functioning is rare, but a few researchers have tried to explain the factors involved in long-term graft survival. In this report, we explore the predictive factors that can be involved in ultralong-term graft survival. MATERIAL AND METHODS: Immunologic evaluations of the patients were performed using crossmatch (XM), serological, and high-resolution HLA typing for 8 loci. A transplant recipient was treated with azathioprine as immunosuppressive monotherapy for 42 years. Donor-specific antibodies (DSAs) were identified using panel reactive antibody single antigen beads (PRA-SAB) followed by EpVix and Matchmaker epitope analysis to define the immunogenic mismatch eplets. RESULTS: The patient and donor were haploidentical for 7 loci and identical at the HLA-DPA1* locus. Among 61 identified eplet mismatches, DSAs were not detected against 59 eplets after 42 years of exposure to the patient's immune system with the exceptions of antibodies against the public eplets 9Y and 9YL from allele HLA-DPB1*03:01, and the transplanted kidney exhibited preserved structures. CONCLUSION: The transplanted kidney has the preserved structure based on magnetic resonance imaging, the 2 DSAs were not deleterious to the graft until now, and the eplet mismatches were considered acceptable. The patient is in good clinical condition living with a 100-year-old graft, a serum creatinine level of 1.5 mg/dL, and an estimated glomerular filtration rate of 50 mL/1.72 m2.

A novel HLA allele, HLA-A*29:01:08, identified in a Brazilian individual.

HLA-A*29:01:08 differs from A*29:01:01:01 by a single synonymous substitution at position 519, codon 149 GCG→GCA in exon 3.

A novel HLA allele, HLA-DRB1*13:204, detected in a Brazilian unrelated hematopoietic stem cell donor.

The HLA-DRB1*13:204 allele differs from HLA*13:64 by two nucleotide substitutions at positions 181 and 189 in the exon 2.

The heterogeneous HLA genetic composition of the Brazilian population and its relevance to the optimization of hematopoietic stem cell donor recruitment.

The aim of this study was to investigate the human leukocyte antigen (HLA) molecular variation across the Brazilian population in order to determine possible regional differences, which would be highly relevant to optimizing donor recruitment strategies in hematopoietic stem cell transplantation (HSCT) and understanding the population genetic background of this heterogeneous country. HLA data of 551 HSCT donors from five Brazilian regions were characterized by high-resolution DNA alleles at the HLA-A, -B, -C, -DRB1 and -DQB1 loci and compared with other populations in Brazil and worldwide populations. Allele and haplotype frequencies were estimated. The analysis was performed to assess Hardy-Weinberg equilibrium (HWE) and linkage disequilibrium (LD) among different loci in each recruitment center. Genetic variation was explored through genetic distance analyzed by using a new algorithm based on linear algebra, taking into account geographic regions of Brazil. The results indicated a heterogeneous genetic composition of the Brazilian population, such that HLA allele and haplotype frequencies exhibit different distributions among Brazilian regions, which has important implications for donor matching. In addition, a pronounced differentiation was observed by the absence of clustering of the regional populations in the reduced-dimension space. These data may be useful for increasing donor recruitment with more genetic representativeness in the Brazilian Volunteer Bone Marrow Donors Registry (REDOME).

Description of five novel HLA-B alleles, B*07:184, B*41:27, B*42:19, B*50:32 and B*57:63, identified in Brazilian individuals.

Five novel HLA-B alleles were identified by HLA-SBT typing in seven unrelated Brazilian individuals. The new alleles discovered include HLA-B*07:184, B*41:27, B*42:19, B*50:32 and B*57:63 and were officially named by the World Health Organization (WHO) Nomenclature Committee. All new HLA-B alleles had nonsynonymous nucleotide substitution polymorphisms when compared to their most closely related HLA-B allele.

Four novel HLA alleles, DRB1*04:11:03, DRB1*10:05, DRB1*15:94 and DRB1*16:22, identified in Brazilian individuals.

Four novel human leucocyte antigen (HLA) class II alleles were identified by sequencing-based typing (SBT) and analysis of the closest-matching alleles from volunteer subjects from the Brazilian Bone Marrow Donor Register (REDOME, Brazil). The new HLA alleles discovered include DRB1*04:11:03, DRB1*10:05, DRB1*15:94 and DRB1*16:22. Three of the novel alleles had single-nucleotide substitution polymorphisms when compared to their most homologous allele. Of these, one harboured a single-nucleotide polymorphism (SNP) identified as a silent substitution.

Description and molecular modeling of four novel HLA-B alleles identified in Brazilian individuals.

Four novel HLA-B alleles, B*42:20, B*51:151, B*57:64 and B*58:42 were identified in Brazilian individuals.

A novel HLA allele, HLA-A*80:03, identified in a Brazilian individual.

The HLA-A*80:03 allele differs from HLA*80:01:01:01 by two nucleotide substitutions at positions 559 and 560 in the exon 3.

Identification of a novel HLA-B allele, B*27:102, in a Brazilian individual.

The HLA-B*27:102 allele may have originated by an intralocus gene conversion event.