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Background Tacrolimus (TAC) is a key immunosuppressant drug for kidney transplantation (KTx). However, the optimal serum trough level of TAC for good long-term outcomes remains unclear. This study aimed to investigate the relationship between the maintenance TAC trough level and the appearance of de novo donor-specific anti-human leukocyte antigen (HLA) antibodies (dn DSAs). Methods A total of 584 KTx recipients were enrolled in this study, of whom 164 developed dn DSAs during the follow-up period and 420 did not. Results We found no significant relationship between TAC trough level during the follow-up period and dn DSA incidence. Patients who developed dn DSAs had a significantly greater number of HLA-A/B/DR mismatches (3.4 ± 1.3 versus 2.8 ± 1.5; P < 0.001), were more likely to have preformed DSAs (48.2% versus 27.1%; P < 0.001) and showed poor allograft outcome. Conclusions There was no clear relationship between TAC trough level and dn DSA incidence for KTx recipients whose TAC trough levels were kept within the narrow range of 4–6 ng/mL during the immunosuppression maintenance period. [ABSTRACT FROM AUTHOR]

Aim Transplant glomerulopathy ( TG) is included as one of the criteria of chronic active antibody-mediated rejection (c- AMR) in Banff 09 classification. In this report, we discuss the clinical and pathological analyses of cases of TG after renal transplantation. Patients TG was diagnosed in 86 renal allograft biopsy specimens ( BS) obtained from 50 renal transplant patients followed up at our institute between January 2006 and October 2012. We retrospectively reviewed the data of these 86 BS and 50 patients. Results Among the 50 patients, 42 (84%) had a history of acute rejection ( AR); of these, 30 (60%) had acute antibody-mediated rejection (a- AMR). Among the 86 BS of TG, the TG was mild in 35 cases (cg1 in Banff classification), moderate in 28 cases (cg2) and severe in 23 cases (cg3). Peritubular capillaritis was present in 74 BS (86%), transplant glomerulitis in 65 (76%), interstitial fibrosis and tubular atrophy ( IF/ TA) in 71 (83%), thickening of the peritubular capillary ( PTC) basement membrane in 72 (84%), and interstitial inflammation in 40 (47%). C4d deposition in the PTC was present in 49 BS (57%); 39 of these 49 BS showed diffuse C4d deposits in the PTC ( C4d3), while the remaining 10 BS showed focal deposits ( C4d2). Diffuse C4d deposition in the glomerular capillaries ( GC) was seen in 70 BS (81%), while focal C4d deposition in the GC was seen in 9 (11%). In the assay using plastic beads coated with HLA antigen performed in 67 serum samples obtained in the peri-biopsy period, circulating ant- HLA alloantibody was detected in 55 (82%); in 33 of the 55 (49%) samples, donor-specific antibodies ( DSA) were detected. Among our study, the findings in 22 BS (26%) fully met the criteria for c- AMR in Banff '09 classification, including TG, C4d deposition in the PTC and presence of DSA, while those in 27 BS were suspicious of c- AMR. Deterioration of the renal allograft function after the biopsies was seen in 31 patients (62%), of which 11 lost their graft. Conclusions We suggest that histopathological changes of transplant glomerulopathy might be accompanied by inflammation of the microvasculature, such as transplant glomerulitis and peritubular capillaritis, thickening of the peritubular capillary basement membrane, and circulating anti- HLA antibodies. C4d deposition in the PTC is not always present in biopsy specimens of TG. We speculated that C4d deposition in the GC, rather than that in the PTC might be a more characteristic manifestation of TG. Many of the patients with TG had a history of AR. Anti- HLA antibody Class II, particularly when the antibody was DSA Class II, appeared to be associated with the development of TG. The prognosis of grafts exhibiting TG was not too good even under the currently used immunosuppressive protocol. [ABSTRACT FROM AUTHOR]

Abstract: The number of immunoglobulin heavy chain (IGH) constant genes (IGHC) varies among mammals. To annotate the porcine IGHC genes, we sequenced the entire IGHC-containing genomic region from a single porcine haplotype. The resulting contiguous sequence included in 5′ the IGH diversity (D) gene cluster and in 3′ TMEM121, which flank the IGHC cluster in the human genome, suggesting that we had obtained the entire genomic region containing porcine IGHC. This region was about 190-kb long, in good agreement with those of other mammals. The porcine IGHC cluster contained 10 genes, IGHM, IGHD, six IGHG genes, IGHE and IGHA. The porcine IGHG genes formed a cluster between IGHD and IGHE, with IGHG3 considered as the most ancient IGHG gene, located at the beginning of the IGHG cluster. Furthermore, the porcine sequence contained two IGHG5 and two IGHG6 genes, but no IGHG genes for IgG2 and IgG4, suggesting flexibility within the IGHG cluster. We also recorded structural differences in the switch regions of the IGHC genes that may be important in their transcription. This haplotype can serve as a reference for future studies on other haplotypes and for functional analysis of porcine immunoglobulin (IG) isotypes. [Copyright &y& Elsevier]

Honda K, Horita S, Toki D, Taneda S, Nitta K, Hattori M, Tanabe K, Teraoka S, Oda H, Yamaguchi Y. De novo membranous nephropathy and antibody-mediated rejection in transplanted kidney. Clin Transplant 2011: 25: 191-200. © 2010 John Wiley & Sons A/S. The etiology of de novo membranous nephropathy (MN) after kidney transplantation is still uncertain. Immunological response to various allograft antigens is speculated to be a candidate for the etiology. Seventeen patients with post-transplant de novo MN were studied clinically and pathologically in comparison with control post-transplant patients without MN. Double immunofluorescent staining was performed to identify the presence of donor-specific human leukocyte antigen (HLA) combined with IgG in the deposits on glomerular capillary walls. De novo MN occurs in relatively late period after transplantation (102.1 ± 68.3 months), presenting various degree of proteinuria. Histological findings associated with antibody-mediated rejection (AMR), such as peritubular capillaritis and C4d deposition in peritubular capillary, were more frequently observed in the patients with de novo MN than the non-MN control patients. Donor-specific antibody (DSA) was detected in five patients at the time of biopsy. In one case of de novo MN with DSA, a donor-derived HLA was identified in the subepithelial deposits on the glomerular capillary walls combined with IgG deposition. DSA and AMR might play some roles for the pathogenesis in some patients with de novo MN after kidney transplantation. [ABSTRACT FROM AUTHOR]