岩見 大基

Chronic allograft rejection is the most common cause of long-term allograft failure. One reason is that current diagnostics and therapeutics for chronic allograft rejection are very limited. We here show that enhanced NFκB signaling in kidney grafts contributes to chronic active antibody-mediated rejection (CAAMR), which is a major pathology of chronic kidney allograft rejections. Moreover, we found that urinary orosomucoid 1 (ORM1) is a candidate marker molecule and therapeutic target for CAAMR. Indeed, urinary ORM1 concentration was significantly higher in kidney transplant recipients pathologically diagnosed with CAAMR than in kidney transplant recipients with normal histology, calcineurin inhibitor toxicity, or interstitial fibrosis and tubular atrophy. Additionally, we found that kidney biopsy samples with CAAMR expressed more ORM1 and had higher NFκB and STAT3 activation in tubular cells than samples from non-CAAMR samples. Consistently, ORM1 production was induced after cytokine-mediated NFκB and STAT3 activation in primary kidney tubular cells. The loss- and gain-of-function of ORM1 suppressed and promoted NFκB activation, respectively. Finally, ORM1 enhanced NFκB-mediated inflammation development in vivo. These results suggest that an enhanced NFκB-dependent pathway following NFκB and STAT3 activation in the grafts is involved in the development of chronic allograft rejection after kidney transplantation and that ORM1 is a non-invasive candidate biomarker and possible therapeutic target for chronic kidney allograft rejection.

BACKGROUND: Rituximab (RIT) is effective as a part of the desensitization therapy before ABO-incompatible kidney transplantation (ABOi-KTx), and a single dose of RIT at 375 mg/m2 or less is recommended. However, adequate RIT dose recommendations have not yet been established for individual recipients. Therefore, we evaluated the relationship between the proportion of B cells in peripheral blood and acute antibody-mediated rejection (AAMR). METHODS: Forty-four consecutive ABOi-KTx recipients were enrolled in this retrospective study. Before transplantation, subjects were treated with RIT at various doses, ranging from 65 to 400 mg/body (46-263 mg/m2), followed by plasmapheresis and intravenous immunoglobulin as a desensitization therapy. The percentage of CD19+ cells in the total peripheral blood lymphocytes population (%CD19) was determined the day before transplantation. Transplant recipients were divided into 2 groups according to pretransplant %CD19, as follows: low %CD19 group, ≤ 1.2% (n = 35) and high %CD19 group, > 1.2% (n = 9). The relationship between %CD19 and incidence of AAMR was evaluated, and the predicting factors for AAMR incidence were determined by univariate and multivariate analyses. RESULTS: The incidence of AAMR was significantly higher in the high %CD19 group than in the low %CD19 group (44.4% vs 5.7%, P = .006). Furthermore, multivariate analysis showed that %CD19 > 1.2% was the only independent factor to predict AAMR, with an odds ratio of 14.31 (P = .038). CONCLUSION: High %CD19 values after rituximab administration in ABOi-KTx recipients implies insufficient depletion of B cells, which can lead to AAMR.

BACKGROUND: Multiple renal arteries are found in approximately 20% of living donor kidneys. We have been using an accessory artery cutoff diameter of 2 mm on preoperative computed tomography angiography to determine whether to sacrifice or reconstruct the artery. In this study, we assessed the validity and feasibility of this cutoff value. METHODS: Living related kidney recipients from 2005 to 2013 were enrolled in this retrospective study. The diameter of the accessory artery and adverse events were evaluated. The lost parenchymal volume (%) due to vascular obstruction or branch ligation was calculated by computed tomography volumetry. RESULTS: Among 128 kidney transplants, 30 donor kidneys had multiple arteries. Accessory arteries were reconstructed in 18 cases and intentionally ligated in 12 cases (mean diameter of accessory arteries, 3.10 [SD, 0.75] mm and 1.81 [SD, 0.28] mm, respectively). The mean estimated glomerular filtration rate at 1 or 12 months after transplant was not significantly different between the groups. Among reconstructed cases, 14 cases (77.8%) had good patency in the reconstructed arteries whereas the other 4 had vascular complications. The percentage of lost parenchymal volume due to ligation or occlusion of the reconstructed artery (calculated in 16 cases) was predictable with the following formula: lost volume (%) = 9.09 × diameter (mm) - 10.5 (P= .03, rs= 0.533 by Spearman rank correlation coefficient). This formula indicated that ligation of a 2-mm accessory artery leads to 7.68% loss of the renal parenchyma. CONCLUSIONS: Reconstruction using a cutoff diameter of 2 mm is worth attempting in terms of the success rate and graft function. Sacrifice of a 2-mm accessory artery leads to parenchymal loss of <8%.