Naohiko Shimoda

CXC Chemokine Ligand (CXCL) 9 and CXCL10 Are Antagonistic Costimulation Molecules during the Priming of Alloreactive T Cell Effectors

Donor Ag-reactive CD4 and CD8 T cell production of IFN-γ is a principal effector mechanism promoting tissue injury during allograft rejection. The CXCR3-binding chemokines CXCL9 and CXCL10 recruit donor-reactive T cells to the allograft, but their role during the priming of donor-reactive T cells to effector function is unknown. Using a murine model of MHC-mismatched cardiac transplantation, we investigated the influence of CXCL9 and CXCL10 during donor-reactive T cell priming. In allograft recipient spleens, CXCL9 and CXCL10 were expressed as early as 24 h posttransplant and increased with similar kinetics, concurrently with CXCR3 expression on T cells. CXCL9, but not CXCL10, expression required NK cell production of IFN-γ. The absence of CXCL9 in donor allografts, recipients, or both significantly decreased the frequency of donor-reactive CD8 T cells producing IFN-γ and increased the frequency of donor-reactive CD8 T cells producing IL-17A. In contrast, the absence of CXCL10 increased the frequency of IFN-γ–producing CD8 T cells in a CXCL9-dependent manner. These data provide novel evidence that donor-reactive CD8 T cells use the CXCR3 chemokine axis as a costimulation pathway during priming to allografts where CXCL9 promotes the development of IFN-γ–producing CD8 T cells, and CXCL10 antagonizes this skewing.

Donor-specific antibody in chronic rejection is associated with glomerulopathy, thickening of peritubular capillary basement membrane, but not C4d deposition

Abstract:  The impact of post‐transplant donor‐specific antibody (DSA) on the development of chronic rejection has been focused recently. The aim of this study was to evaluate the significance of DSA, graft function and pathological factors of chronic rejection. Seventy‐three kidney recipients who underwent protocol biopsy were included in the study. The median follow‐up period after transplant was 40 months. The presence of anti‐HLA antibody (aHLAAb) and DSA was tested using flow beads analysis (FlowPRA®). The patients were divided into a group with DSA, a group with non‐donor‐specific aHLAAb and a group without aHLAAb. Protocol biopsy specimen were compared for transplant glomerulopathy (cg), vasculopathy (cv), C4d deposition at peritubular capillary (PTC), peritubular capillaritis (ptc score 0–3) and thickening of PTC basement membrane (ptcbm score 0–3) as recently proposed. The presence of DSA was significantly associated with the presence of cg, ptcbm. The group with non‐donor‐specific aHLAAb had ptcbm but did not have cg. The group without aHLAAb rarely showed ptcbm. The presence of DSA was associated with impaired graft function. C4d was not specific for the patients with DSA. These histopathological markers are useful in the detection of immunological chronic rejection. Early detection by screening tests will be important for treatment before irreversible change occurs.

Lower urinary tract symptoms and their impact on quality of life after successful renal transplantation

Objective:  To investigate lower urinary tract symptoms (LUTS) and their impact on quality of life (QOL) in patients having undergone renal transplantation (RTX).

Pediatric kidney transplantation is safe and available for patients with urological anomalies as well as those with primary renal diseases

Abstract:  The aim of the current study was to evaluate long‐term outcomes of pediatric live kidney transplantation in patients with genitourinary anomalies relative to those with primary kidney diseases. The study included 35 pediatric patients who received a live kidney transplantation during the last 25 yr (28 males, six females). Median age at the time of transplantation was nine yr (range 1–15 yr), and the median follow‐up period was 151 months (range 6–239 month). The patients were divided into two groups. The urological group (n = 14) included patients with primary obstructive/reflux nephropathy. The renal group (n = 20) included patients with primary renal disorders. Differences between groups in graft survival, clinical course, and final graft function were evaluated. Original diseases represented in the urological group included five cases with primary VUR and eight cases with secondary VUR. Diseases in the renal group included eight cases with bilateral hypo‐dysplastic kidney, three cases with focal/segmental glomerular sclerosis, two cases with membranous proliferative glomerulonephritis, two cases with congenital nephrotic syndrome and five cases with other forms of chronic nephritis. Ten of 14 cases in the urological group, relative to six of 20 in the renal group, were preemptive. Median age at transplantation was 7.5 or 10 yr old, respectively, in the urological or renal group. Twelve kidney recipients in the urological group had also undergone other urinary surgeries, including upper urinary tract drainage, ureteroneocystostomy, augmentation cystoplasty, endoscopic incision of posterior‐urethral valve, urethroplasty, etc. Cumulative post‐operative complications occurred in nine or 16, respectively, in the urological or renal group. The acute rejection free and overall graft survival were similar in both groups. One patient in the urological group lost his graft while six patients in the renal group lost their grafts. Thus, the post‐transplant clinical outcome of pediatric transplantation in patients with urological anomalies is comparable to that of recipients with primary renal disease. Appropriate urinary tract reconstruction and management is essential to reduce the risk of graft dysfunction because of urinary problems.

A case of progressive thrombotic microangiopathy after ABO-incompatible renal transplantation

Miura M, Fujita H, Suzuki A, Kubota KC, Fukasawa Y, Shimoda N, Tsuchihashi S, Tamaki T. A case of progressive thrombotic microangiopathy after ABO‐incompatible renal transplantation.
Clin Transplant 2011: 25 (Suppl. 23): 19–22.
© 2011 John Wiley & Sons A/S.

A case of plasmacytic hyperplasia arising in a kidney allograft salvaged with immunosuppression reduction alone.

Abstract:  Post‐transplant lymphoproliferative disorder (PTLD) is a well‐known complication of organ transplantation. Plasmacytic hyperplasia (PH) is thought of as the mildest form of PTLD; however, a graftectomy is necessary in most situations. We experienced an interesting case of PH arising in a kidney allograft, which could be relieved with a reduction in immunosuppression. A 27‐year‐old female underwent a living‐related kidney transplantation. A 3‐month non‐episode protocol biopsy unexpectedly showed the devastating appearance of polymorphic plasma cell infiltration into the graft intersitium, compatible with PH. The PH was located in the graft by radiographic examinations. The infiltration of plasma cell disappeared completely on the 6‐month graft biopsy specimen following immunosuppression reduction and the graft is functioning, although it was damaged by a subsequent acute rejection. Our present case indicates that some PTLD can be completely cured with a reduction in immunosuppression alone. The diagnostic modality for the evaluation of PTLD cell extinction is necessary to maintain graft function with adequate immunosuppression thereafter.

Clinicopathologic evaluation of short-term outcome after early corticosteroid discontinuation in kidney transplantation

Abstract: Objectives:  Steroids have been a gold‐standard drug of immunosuppressive regimens in kidney transplantation. Steroid minimization protocols have been applied to minimize the adverse effects of steroids. We have evaluated the short‐term outcomes of our early steroid discontinuation regimen.

The difference in histopathology of antibody-mediated rejection between ABO incompatible and pre-sensitized cases

Abstract:  Suppression of antibody‐mediated rejection (AMR) is mandatory for the acceptance of renal allograft in ABO blood type incompatible and pre‐sensitized combinations. The aim of this study was to evaluate the difference in histopathology of AMR between ABO incompatible (ABOI) and pre‐sensitized cases. Among 69 kidney recipients who underwent transplant surgery at our institute since 2002, four patients who manifested AMR were included in this study. They initially received quadrant immunosuppressants, tacrolimus, mycophenolate mofetil, methylprednisolone and basiliximab. Two patients received grafts from ABOI donors and the other two received grafts from flow T‐cell crossmatch‐positive donors. Although satisfying antibody removal was achieved by pre‐transplant plasmapheresis, all four cases manifested acute AMR, within two wk post‐transplant. Antibody titer and panel reactive antibody increased at the time of AMR. ABOI cases showed slight cellular infiltration. These cases showed diffuse, strong and linear deposition of C4d at peritubular capillaries (PTC). On the other hand, pre‐sensitized cases showed more intense cellular infiltration, especially in glomerulus but only faint and focal deposition of C4d at PTC. All four cases were treated with corticosteroid pulse therapy in conjunction with several sessions of plasmapheresis.