岩見 大基

BACKGROUND: Thrombotic microangiopathy (TMA) after kidney transplantation (KTx), particularly early onset de novo (dn) TMA, requires immediate interventions to prevent irreversible organ damage. This multicenter study was performed to investigate the allogeneic clinical factors and complement genetic background of dnTMA after KTx. METHODS: Perioperative dnTMA after KTx within 1 week after KTx were diagnosed based on pathological or/and hematological criteria at each center, and their immunological backgrounds were researched. Twelve aHUS-related gene variants were examined in dnTMA cases. RESULTS: Seventeen recipients (15 donors) were enrolled, and all dnTMA cases were onset within 72-h of KTx, and 16 of 17 cases were ABO incompatible. The implementation rate of pre-transplant plasmaphereses therapies were low, including cases with high titers of anti-A/anti-B antibodies. Examination of aHUS-related gene variants revealed some deletions and variants with minor allele frequency (MAF) in Japan or East Asian genome databases in genes encoding alternative pathways and complement regulatory factors. These variants was positive in 8 cases, 6 of which were positive in both recipient and donor, but only in one graft loss case. CONCLUSIONS: Although some immunological risks were found for dnTMA after KTx, only a few cases developed into TMA. The characteristic variations revealed in the present study may be novel candidates related to dnTMA in Japanese or Asian patients, but not pathogenic variants of aHUS. Future studies on genetic and antigenic factors are needed to identify factors contributing to dnTMA after KTx.

BACKGROUND: Non-invasive, prompt, and proper detection tools for kidney graft injuries (KGIs) are awaited to ensure graft longevity. We screened diagnostic biomarkers for KGIs following kidney transplantation using extracellular vesicles (EVs; exosomes and microvesicles) from the urine samples of patients. METHODS: One hundred and twenty-seven kidney recipients at 11 Japanese institutions were enrolled in this study; urine samples were obtained prior to protocol/episode biopsies. EVs were isolated from urine samples, and EV RNA markers were assayed using quantitative reverse transcription polymerase chain reaction. Diagnostic performance of EV RNA markers and diagnostic formulas comprising these markers were evaluated by comparison with the corresponding pathological diagnoses. RESULTS: EV CXCL9, CXCL10, and UMOD were elevated in T-cell-mediated rejection samples compared with other KGI samples, while SPNS2 was elevated in chronic antibody-mediated rejection (cABMR) samples. A diagnostic formula developed through Sparse Logistic Regression analysis using EV RNA markers allowed us to accurately (with an area under the receiver operator characteristic curve [AUC] of 0.875) distinguish cABMR from other KGI samples. EV B4GALT1 and SPNS2 were also elevated in cABMR, and a diagnostic formula using these markers was able to distinguish between cABMR and chronic calcineurin toxicity accurately (AUC 0.886). In interstitial fibrosis and tubular atrophy (IFTA) urine samples and those with high Banff chronicity score sums (BChS), POTEM levels may reflect disease severity, and diagnostic formulas using POTEM detected IFTA (AUC 0.830) and high BChS (AUC 0.850). CONCLUSIONS: KGIs could be diagnosed with urinary EV mRNA analysis with relatively high accuracy.

Donor-specific antibodies (DSAs) are the main cause of graft loss over time. The direct pathway of alloantigen recognition is important in the pathogenesis of acute rejection. Recent studies have suggested that the direct pathway also contributes to the pathogenesis of chronic injury. Nevertheless, there are no reports on T-cell alloantigen response via the direct pathway in kidney recipients with DSAs. We analyzed the T-cell alloantigen response via the direct pathway in kidney recipients with DSAs (DSA+) or without DSAs (DSA-). A mixed lymphocyte reaction assay was implemented to assess the direct pathway response. DSA+ patients showed significantly higher CD8+ and CD4+ T cell responses to donor cells than DSA- patients. Furthermore, proliferating CD4+ T cells showed a marked increase in Th1 and Th17 responses in DSA+ patients than in DSA- patients. In a comparison between anti-donor and third-party responses, the anti-donor CD8+ and CD4+ T cell response was significantly lower than the anti-third-party response. In contrast, the donor-specific hyporesponsiveness was absent in DSA+ patients. Our study demonstrated that DSA+ recipients have a greater potential for developing immune responses against the donor tissues via the direct alloantigen recognition pathway. These data contribute to an understanding of DSAs pathogenicity during kidney transplantation.

Donors with resolved hepatitis B virus (HBV) infection may be a solution for the organ shortage for kidney transplantation (KT). The purpose of this study was to clarify the current state of HBV markers after KT from donors with resolved HBV infection to HBV naïve recipients and the rate of HBV reactivation in recipients with resolved HBV infection. Furthermore, we investigated HBV covalently closed circular DNA (cccDNA) in transplanted organs from donors with resolved HBV infection and the capability of HBV replication in kidney cell lines. We retrospectively analysed the HBV status of 340 consecutive donors and recipients who underwent KT in a single centre. We prospectively measured cccDNA by real-time polymerase chain reaction in kidney biopsy specimens of 32 donors with resolved HBV infection. HBV reactivation was found in three recipients with resolved HBV infection (4.8%, 3/63) after KT. We analysed 45 cases of transplantation from donors with resolved HBV infection to HBV-naive recipients. One case (2.2%, 1/45) became seropositive for hepatitis B core antibody (anti-HBc) and in another case (2.2%, 1/45), HBV-DNA was detected qualitatively in an HBV naive recipient with a donor with resolved HBV infection. In the latter case, cccDNA was measured in the donor kidney during KT. HBV replication was observed in kidney cell lines with HBV plasmid transfection. In conclusion, the risk of reactivation in anti-HBc-positive donors is relatively low. However, post-transplant HBV monitoring should be conducted in all at-risk cases.

Introduction: We present a case of urothelial carcinoma in a renal allograft successfully treated with pembrolizumab. Case presentation: A 39-year-old woman presented with nausea and anorexia 9 years after a renal transplantation. Positron emission tomography revealed a neoplasm of the renal pelvis of the allograft and multiple lymph nodes with peritoneal metastasis. A diagnosis of a non-muscle-invasive bladder tumor with peritoneal dissemination and jejunal metastasis of urothelial carcinoma was made. After five cycles of gemcitabine and carboplatin, the tumor progressed and pembrolizumab was administered. One week after the first dose, the allograft was rejected, necessitating arterial embolization. After the second cycle, the patient developed Stevens-Johnson syndrome. After discontinuing pembrolizumab, positron emission tomography revealed no increased tumor activity. A complete response was achieved for 21 months without additional treatment. Conclusion: Pembrolizumab was effective in treating urothelial carcinoma of the renal allograft; however, allograft rejection and loss should be considered.

We report a case of bladder cancer in a 54-year-old woman who underwent renal transplantation for chronic renal failure. Six years after the transplantation, she was diagnosed with muscle-invasive bladder cancer with multiple lung metastases. She received gemcitabine/cisplatin therapy for Stage IV bladder cancer, and the dose of the immunosuppressants was reduced to prevent adverse effects. Since lung metastatic lesions disappeared after four courses of chemotherapy and no new lesions were found, we performed radical cystectomy and right nephroureterectomy with ileal conduit construction. Although she was followed closely without therapy, multiple lung metastases appeared 6 months after the radical cystectomy. Gemcitabine/carboplatin therapy was administered, and the lung metastasis improved slightly until the end of the 4th course, but aggressive growth was observed after the 5th course. She switched to palliative treatment without requesting additional treatment and died of cancer 1 year and 9 months after total cystectomy.There is no evidence-based treatment strategy for advanced bladder cancer after kidney transplantation. It is necessary to recognize that the patient had renal dysfunction and was in an immunosuppressed state. Thus, it is crucial to select appropriate drug and surgical treatments for each patient.

症例は54歳女性,原疾患不明の慢性腎不全に対して献腎移植を施行され腎機能は安定していた.移植後6年で膀胱刺激症状を契機に膀胱右側の筋層浸潤性膀胱癌が判明し肺転移も伴っていた.StageIV膀胱癌として免疫抑制剤を減量しゲムシタビン・シスプラチン療法を開始したところ,4コース後に転移巣が消失した.新規病変を認めなかったため開放手術にて右腎尿管膀胱全摘術および回腸導管造設を行った.摘出標本で左尿管断端に上皮内癌病変を認めたため,2ヵ月後に残存した左固有腎尿管に対して鏡視下で腎尿管全摘術を施行したが,悪性所見は認めなかった.Surgical CRとして無治療経過観察としたが,術後半年で多発肺転移が出現した.ゲムシタビン・カルボプラチン療法を導入し,4コース終了までは肺転移がやや縮小したが,5コース終了後は増悪を認めていた.追加治療を希望せず緩和治療へ移行となり膀胱全摘後1年9ヵ月で癌死した.腎移植後であっても膀胱全摘および尿路変向手術は可能で,免疫抑制剤の調整により化学療法も完遂できた.腎移植後の進行性膀胱癌にエビデンスのある治療方針はなく,腎機能障害を有し免疫抑制状態であることを認識し,個々の症例で適切な薬物治療や外科的治療の選択をする必要がある.(著者抄録)

Background: A positive flow-cytometry T cell crossmatch (FTXM) has important prognostic implications, even when the complement-dependent cytotoxicity crossmatch is negative. Recent studies have shown that ABO incompatibility is associated with positive FTXM, but the underlying mechanism remains poorly understood. Cases: In five ABO blood type O recipients of kidneys from wives with type B, FTXM was positive but complement-dependent cytotoxicity crossmatch was negative. Application of a solid-phase technique (LABScreen) revealed no case with antibodies to donor-specific human leukocyte antigen. After removal of type B antibodies from patient sera, FTXM was negative for all five patients. In one tested case, the eluate prepared from the donor's T lymphocyte agglutinated only type B red blood cells, implying the existence of blood type B substances on donor T lymphocytes. Discussion: False-positive FTXM reflects blood type B substrates bound to T lymphocytes. Repeat FTXM after incubation with donor-type red blood cells (to adsorb anti-ABO antibodies) was negative. This phenomenon explains the discrepancy between FTXM and solid-phase bead assays. Demonstration of type B substances on donor T lymphocytes is necessary before absolute test validity is confirmed. Conclusion: False-positive FTXM may be associated with type B antibodies bound to T lymphocytes when a blood type O recipient receives tissue from a type B donor. This phenomenon explains the false-positive FTXM observed in the setting of ABO-incompatible kidney transplantation.

Surgical training using live animals such as pigs is one of the best ways of achieving skilled techniques and fostering confidence in preclinical medical students and surgeon trainees. However, due to animal welfare ethics, laboratory animals' usage for training should be kept to a minimum. We have developed a novel kidney organ model utilizing a simple procedure in which the kidney is first refluxed with N-vinyl-2-pyrrolidone (NVP) solution for 1 hour in its bath, followed by permeation for 23 hours, with a subsequent freshwater refluxed for 48 hours in the washing step. Surgical simulation of the prepared kidney model (NVP-fixed kidney) was compared with three types of other basic known simulation models (fresh kidney, freeze-thaw kidney, and FA-fixed kidney) by various evaluations. We found the NVP-fixed kidney to mimicked fresh kidney function the most, pertaining to the hardness, and strength of the renal parenchyma. Moreover, the NVP-fixed kidney demonstrated successful blood-like fluids perfusion and electrocautery. Further, we confirmed that surgical training could be performed under conditions closer to actual clinical practice. Our findings suggest that our model does not only contribute to improving surgical skills but also inspires the utilization of otherwise, discarded inedible livestock organs as models for surgical training.

Background: Removal of anti-blood group antibodies is important for successful ABO-incompatible kidney transplantation (ABOi-KTx). Double-filtration plasmapheresis (DFPP) using albumin solution removes antibodies effectively. However, fibrinogen is largely removed resulting in hemostatic failure. Herein, we designed an altered combination of plasma membranes in DFPP (novel DFPP, nDFPP) to retain more fibrinogen while removing IgG, and assessed its efficacy and safety compared with conventional DFPP (cDFPP). Methods: Consecutive ABOi-KTx recipients (from 2015 to 2018) were enrolled. For the first membrane, we used Cascadeflo EC-50W in nDFPP and Plasmaflo OP-08W in cDFPP, and Cascadeflo EC-20W as the second membrane in both modalities. Removal rates (RR) of IgG, IgM and fibrinogen per DFPP session, and adverse events were compared with historical control patients who underwent cDFPP before ABOi-KTx, between 2006 and 2015. Results: nDFPP and cDFPP groups included 12 and 23 cases, respectively. nDFPP was inferior to cDFPP in RR of IgG and IgM. nDFPP was also inferior to cDFPP in the decline in anti-blood group IgG and IgM antibody titers. However, fibrinogen was more preserved in nDFPP compared with cDFPP, indicating that nDFPP has more selective removal properties (median RR of IgG, IgM, and fibrinogen: 62.1%, 15.7% and 37.6%, respectively, in nDFPP; and 74.5%, 85.0% and 76.6%, respectively, in cDFPP). In the comparison of hemostatic function among the patients who had arteriovenous fistula for hemodialysis, prolonged hemostasis (> 20 min) at the cannulation site was significantly less frequently observed in nDFPP group (1 in 9 cases, 9.1%) than in cDFPP group (all 18 cases, 10%, p < 0.0001). Conclusions: nDFPP preserves fibrinogen while removing anti-blood type IgG antibodies before ABOi-KTx.

<title>Abstract</title><sec> <title>Background</title> Simultaneous pancreas and kidney transplantation (SPK) is a treatment option for patients with end-stage renal disease due to type 1 diabetes mellitus. We report a patient with a refractory fistula due to leakage from the duodenal stump of the pancreas graft after an SPK with bladder drainage who was successfully treated with a percutaneous direct injection of <italic>N</italic>-butyl-2-cyanoacrylate (NBCA). </sec><sec> <title>Case presentation</title> A 60-year-old female with a 33-year history of type 1 diabetes mellitus and a 10-year history of renal replacement therapy underwent an SPK in 2015. At the time of transplantation, an abdominal aortic aneurysm with a high risk of rupture was treated by a Y-graft replacement prior to the SPK. Bladder drainage of the pancreas graft was chosen to avoid a vessel graft infection. The patient’s postoperative course was uneventful. The patient was discharged on postoperative day 93 with good-functioning pancreas and kidney grafts. One and a half years after the operation, the patient was found to have acute graft pancreatitis and a leak from the duodenal stump of the pancreas graft due to a paralytic neurogenic bladder. The insertion of an indwelling catheter into the bladder and the endoscopic-guided insertion of a catheter into the graft pancreatic duct through the duodenum/bladder anastomosis did not result in the closure of the fistula. Therefore, NBCA was injected at the site of the leak point using CT-guided technique. The fistula was completely closed immediately after the injection, with no recurrences of leaks. </sec><sec> <title>Conclusions</title> A percutaneous direct injection of NBCA is one of the treatment options to treat intractable fistulas. </sec>

Herein we report the case of a 37-year-old woman with recurrence of lupus nephritis (LN) in a renal allograft during pregnancy. She had developed end-stage renal disease due to LN and was put on hemodialysis at the age of 26 years. She underwent kidney transplantation at the age 28 years. Maintenance immunosuppressants included methylprednisolone, tacrolimus, and mycophenolate mofetil, which were changed to azathioprine when she desired pregnancy. The renal allograft function remained stable and seemingly disease-free until proteinuria and functional decline occurred during the pregnancy (age: 34 years). The baby was delivered by performing a cesarean section at 33 weeks of gestation. Renal allograft biopsy revealed crescent formation. Light microscopy revealed tuft necrosis and endocapillary proliferation. Immunofluorescence microscopy revealed the deposition of immunoglobulin G and C1q. A recurrence of LN (ISN/RPS class IV-G [A/C]) was diagnosed, and the patient was treated with pulse steroid therapy and azathioprine was replaced with mycophenolate mofetil. This treatment improved acute or active lesions of LN and temporarily benefited the renal allograft function. Unfortunately, there were irreversible chronic changes and a gradual decline in the renal allograft function.

OBJECTIVES: To evaluate the relationship between the creatinine reduction ratio between postoperative days 1 and 2 and post-transplantation clinical outcomes after living donor kidney transplantation. METHODS: Clinical data of patients who underwent living donor kidney transplantation at Jichi Medical University Hospital, Tochigi, Japan, between 2006 and 2019 were retrieved. The creatinine reduction ratio between postoperative days 1 and 2 was calculated based on the formula: (Cre1 - Cre2) × 100/Cre1; patients were then classified into either the slow graft function (creatinine reduction ratio between postoperative days 1 and 2 ≤30%) or immediate graft function (creatinine reduction ratio between postoperative days 1 and 2 >30%) group. We carried out the log-rank test and multivariate Cox proportional hazards regression analyses to assess graft survival and rejection-free survival, and the unpaired t-test and multivariate linear regression to assess post-transplantation estimated glomerular filtration rates. Multivariate analyses used age, sex, dialysis duration, ABO compatibility, donor-specific antibody positivity and medically complex living donors as explanatory variables. RESULTS: Of the 272 patients, 30 and 242 were in the slow graft function and immediate graft function groups, respectively. Multivariate Cox proportional hazards regression analyses showed a significantly higher incidence of overall and death-censored graft loss in the slow graft function group than the immediate graft function group. The frequency of rejection after 1 week post-transplantation did not differ within the groups. Post-transplantation estimated glomerular filtration rates tended to decline earlier in the slow graft function group than in the immediate graft function group; however, the difference was not statistically significant. CONCLUSIONS: The creatinine reduction ratio between postoperative days 1 and 2 could potentially predict long-term outcomes after living donor kidney transplantation. Using the creatinine reduction ratio between postoperative days 1 and 2 and other conventional indicators might allow accurate risk classification and appropriate therapeutic interventions.

Introduction: After kidney transplantation, patients should be treated with caution and monitored for surgical complications. Among the possible surgical complications, strangulation ileus after kidney transplantation is rare. Case presentation: A 59-year-old woman who had undergone kidney transplantation at 41 years of age presented to our hospital with lower abdominal pain. She was diagnosed with strangulation ileus and underwent emergency surgery. In the lower right abdomen, the small intestine was compressed by cord-like tissue running from the intraperitoneal space to the retroperitoneal space. We confirmed that the cord-like tissue was the ureter of the transplanted kidney. The necrotic small intestine was resected, and ureter-ureteral anastomosis of the ureter of the transplanted kidney was performed. Conclusion: All surgical procedures, including ureteroneocystostomy, require careful attention. The occurrence of some postoperative surgical complications can be prevented by carefully performing the kidney transplantation procedure.

Anemia and vitamin D deficiency are associated with allograft failure, and hence, are potential therapeutic targets among kidney transplant recipients (KTRs). We conducted a multicenter, two-by-two factorial, open-label, randomized clinical trial to examine the effects of anemia correction and vitamin D supplementation on 2-year change in eGFR among KTRs (CANDLE-KIT). We enrolled 153 patients with anemia and >1-year history of transplantation across 23 facilities in Japan, and randomly assigned them to either a high or low hemoglobin target (>12.5 vs. <10.5 g/dl) and to either cholecalciferol 1000 IU/day or control. This trial was terminated early based on the planned interim intention-to-treat analyses (α = 0.034). Among 125 patients who completed the study, 2-year decline in eGFR was smaller in the high vs. low hemoglobin group (i.e., -1.6 ± 4.5 vs. -4.0 ± 6.9 ml/min/1.73 m2 ; P = 0.021), but did not differ between the cholecalciferol and control groups. These findings were supported by the fully adjusted mixed effects model evaluating the rate of eGFR decline among all 153 participants. There were no significant between-group differences in all-cause death or the renal composite outcome in either arm. In conclusion, aggressive anemia correction showed a potential to preserve allograft kidney function.

PURPOSE: Although transplanting two kidneys from a single donor to two recipients has some advantages, the right and left kidneys are not anatomically identical; thus, a surgical procedure considering the anatomical features of the donor kidneys is needed when transplanting them into the opposite renal fossae. Based on vast experience, the surgical details of pig orthotopic kidney transplantation from one donor to two recipients was reported. METHODS: When the right kidney was transplanted to the left renal fossa, the graft was inverted upside down, not backwards, thus ensuring that the anteroposterior relationship of the renal vessels was maintained and anatomically natural vascular anastomosis could be performed. RESULTS: Using this technique, we could have developed a pig experimental model that is safe and has a high success rate, even for researchers in the middle of their training. This technique of inverting the graft upside down was reported in human kidney transplantation to make vascular anastomosis easier. CONCLUSIONS: In pig orthotopic kidney transplantation from one donor to two recipients, an anatomically natural vascular anastomosis could be performed via inverted grafting when the right kidney was transplanted into the left renal fossa.

Introduction: Femoral nerve palsy is a rare but serious complication of kidney transplantation. We report a case of femoral nerve palsy following kidney transplantation and conduct a review of the literature on this complication. Case presentation: A 35-year-old woman with end-stage kidney disease, underwent kidney transplantation in the right iliac fossa. The day after the transplantation, she could not straighten her right leg. Physical examination revealed a paresis of her right quadriceps muscle. The patient's sensation of her right thigh was also impaired. We diagnosed her with femoral nerve palsy caused by inappropriate compression from a self-retaining retractor. Rehabilitation was started immediately. The patient's motor weakness gradually improved, and the patient became able to walk independently 4 weeks later. However, the patient's neuropathic pain sustained 6 months after her kidney transplantation. Conclusion: The improper use of self-retaining retractors can lead to femoral nerve palsy in patients undergoing kidney transplantation.

Chronic active antibody-mediated rejection (CAAMR) is a particular problem in kidney transplantation (KTx), and ~25% of grafts are lost by CAAMR. Further, the pathogenesis remains unclear, and there is no effective cure or marker. We previously found that a hyper NFκB-activating mechanism in non-immune cells, called the IL-6 amplifier, is induced by the co-activation of NFκB and STAT3, and that this activation can develop various chronic inflammatory diseases. Here, we show that synaptotagmin-17 (SYT17) is increased in an exosomal fraction of the urine from CAAMR patients, and that this increase is associated with activation of the IL-6 amplifier. Immunohistochemistry showed that SYT17 protein expression was increased in renal tubule cells of the CAAMR group. While SYT17 protein was not detectable in whole-urine samples by western blotting, urinary exosomal SYT17 levels were significantly elevated in the CAAMR group compared to three other histology groups (normal, interstitial fibrosis and tubular atrophy, and calcineurin inhibitors toxicity) after KTx. On the other hand, current clinical laboratory data could not differentiate the CAAMR group from these groups. These data suggest that urinary exosomal SYT17 is a potential diagnostic marker for CAAMR.

【研究目的】小児献腎移植の臨床経過につき検討する。【対象】北海道大学病院にて小児献腎移植を行った6例(男4、女2)。【結果】年齢は中央値13.4歳(6.2〜17.1)、待機期間は中央値0.9年(0.2〜12)、ドナーは心停止1例、脳死5例であった。3例が2次移植であり、術前透析は血液透析1例、腹膜透析4例、未透析1例であった。1例は下大静脈閉塞による静脈灌流不全で術当日に移植腎摘出となった。他の5例の総阻血時間は中央値494分(356〜616)で、全例術後透析を要さなかった。術後中央値23日(16〜73)で退院し、退院時のクレアチニンは中央値0.5mg/dL(0.4〜2.1)であった。現在術後中央値32ヵ月(10〜100)が経過し、4例は経過良好であるが、1例は術後25ヵ月目に服薬不全にて移植腎機能喪失となった。【結論】小児献腎移植は待機期間が短く、小児腎不全患者の治療法として考慮すべきである。(著者抄録)

症例は18歳、男性。ネフロン癆による腎不全に対し、11歳時に母をドナーとする血液型不一致生体腎移植を施行した。移植1年目、2年目の定期生検で異常所見は認めなかったが、3年目の定期生検で傍尿細管毛細血管(PTC)炎と糸球体炎を認め、PTCにC4dの沈着を認めた。また、HLA Class I、IIのde novoドナー特異的抗体(DSA)が検出されたが、血清クレアチニンの上昇はなくsubclinical antibody-mediated rejection(AMR)と診断した。タクロリムスとミコフェノール酸モフェチルの増量、ステロイドパルス治療、リツキシマブの投与を行った。4年目生検では病理所見の改善とDSAの陰転化を認めた。現在移植後6年11ヵ月経過し、腎機能に悪化はなくDSAの陰転化を維持している。Subclinical AMRに対する治療介入は有効である可能性があり早期診断が重要である。(著者抄録)

【研究目的】移植腎障害(KGI)を非侵襲的に診断しうるバイオマーカーの探索を尿中のエクソソーム・微小嚢胞(EV)中のmRNA解析により行った。【方法】全国11施設にて計127症例の腎移植後の尿検体を集めた。各尿検体からEV RNAを抽出し定量RT-PCR測定を行い、腎生検を含む病理診断結果と比較しマーカー候補遺伝子ならびに複数候補による診断式の診断性能を検証した。【結果】拒絶反応の鑑別では以前に報告したANXA1の上昇は確認できなかったものの、CXCL9、CXCL10、UMODがT細胞性拒絶反応(TCMR)で上昇し、慢性抗体関連拒絶反応(cABMR)ではSPNS2の上昇が確認された。Sparse Logistic Regression(SLR)解析による複数マーカー候補からなる診断式にてcABMRと他のKGI群とAUC 0.875で鑑別できることを確認した。また、臨床上判定が困難な慢性カルシニューリン毒性に比しても、SLR解析でAUC 0.886でcABMRの鑑別が可能であった。加えて、間質線維化・尿細管萎縮や慢性腎障害重症度と相関がみられるマーカー候補POTEMを確認し、SLR解析による診断式でおのおのAUC 0.830、0.850で鑑別できた。【結論】尿中EV RNA解析によりKGIを非侵襲的に診断できうる可能性を示した。(著者抄録)

【研究目的】先天性下部尿路通過障害に起因する慢性腎不全(ESKD)に対する腎移植の成績を検討する。【方法】先天性下部尿路通過障害に起因するESKDにより腎移植を行った男児4症例を対象とし術前後の下部尿路機能および排尿管理と移植腎機能について検討した。【結果】移植時年齢は平均7.4歳であった。閉塞解除後の腎移植前に施行した尿流動態検査では1例で低コンプライアンス膀胱を認め膀胱拡大術を施行され、その後自己導尿管理とした。また、1例では排尿筋過活動を認め抗コリン薬が開始された。他の2例は検査上異常を認めなかったが1例は尿失禁を認め抗コリン薬が開始された。術後の尿路感染症は1例のみで、抗コリン薬を中止した術後13年目に発症し抗コリン薬が再開となった。現在移植後平均14.1年が経過し、拒絶反応の発症はなく、平均のeGFRは48.4mL/minと移植腎機能は良好である。【結論】先天性下部尿路通過障害を有する患者に対する腎移植は、下部尿路機能を評価し適切に管理することにより良好な成績が得られる。(著者抄録)

症例は16歳、男性。出生時にVATER連合と診断され、腎機能障害も認めたため保存期腎不全管理が開始となった。7歳時に腎移植の相談のため当科初診されたが、生体腎移植は両親が糖尿病であり適応外であった。その後、緩徐に腎機能障害が進行し腎代替療法導入が必要な状況となったが、腹膜透析、血液透析は社会背景から困難であり、先行的献腎登録を行った。献腎登録から1年後の16歳時に、脳死ドナーの第一候補に選定され先行的献腎移植を施行した。現在術後1年7ヵ月経過し、腎機能は良好に経過している。本邦において献腎ドナーの数に飛躍的な増加はないが、レシピエント選定基準の変更に伴って小児腎不全患者に優先的に献腎移植できる環境が整いつつある。さらに、先行的献腎移植登録が可能となったため当症例のような先行的献腎移植が可能な状況になった。小児腎不全患者において生体ドナー候補がいない場合には先行的献腎移植登録を考慮すべきである。(著者抄録)

The first reported successful ABO-incompatible kidney transplantation was performed by Alexandre and his colleagues who employed plasma exchange to eliminate ABO antibodies with intensive immunosuppression prior to transplantation. Thereafter, pretransplant desensitization therapy has allowed kidney transplantation across ABO blood type barriers. Most desensitization protocols consist of antibody-producing cells deprivation therapy anti-CD20 monoclonal antibody, rituximab, and/or splenectomy, intensive immunosuppressive treatment, and apheresis to eliminate ABO antibodies. Apheresis is also a treatment option for antibody-mediated rejection after ABO-incompatible kidney transplantation, and the combinational therapy produces excellent graft outcomes. At present, there are three major apheresis modalities to remove ABO antibodies: therapeutic plasma exchange, double-filtration plasmapheresis, and immunoadsorption. Therapeutic plasma exchange is the basic modality of apheresis however, it has potential adverse events associated with using fresh frozen plasma. Double-filtration plasmapheresis was introduced in Japan and aimed to remove molecules with sizes between the two pore sizes of different filtrating membranes. Immunoadsorption is the most selective of the three modalities to eliminate ABO antibodies without supplement fluid.

＜文献概要＞先天性腎尿路異常(CAKUT)は腎尿路における先天異常の総称で,腎,腎盂尿管,膀胱,尿道の多様な疾患を含んでおり,小児の末期腎不全(ESKD)の原因として,もっとも頻度の高い疾患である.低形成腎や異形成腎では小児期にESKDに至る場合が多いが,尿路奇形においては繰り返す尿路感染症(UTI)などにより腎機能障害が進行し,成人になってからESKDに至る場合も多い.そのため,小児期の管理のみならず,成人に達してからの腎臓内科への慢性腎臓病管理の適切な移行と,泌尿器科による長期的な尿路管理によるUTIの予防,腎代替療法の管理が重要である.

【研究目的】腎移植における、慢性抗体関連型拒絶反応(CAAMR)に対する治療の長期成績について検討する。【方法】CAAMRに至った腎移植時15歳以下の4例の治療内容、治療成績について検討した。【結果】診断時期は中央値で移植後5.5年(4.5〜12.4年)であった。全例プロトコール生検で診断された。2症例はステロイドパルス、血漿交換、グスペリムス、リツキシマブ、IVIg投与の多剤併用+抗体除去療法を行った。腎機能は徐々に悪化傾向で、病理学的にCAAMRの進行を認めるが、治療後8年目の現在も生着中である。2症例はリツキシマブ投与のみを行った。1例は治療後4年目も腎機能は安定しており病理学的にも改善を認めたが、もう1例は治療後3年目に移植腎喪失に陥った。【結論】多剤併用+抗体除去療法を行ったCAAMR症例は、長期生着していることより有効な治療である可能性がある。リツキシマブ投与も有効例を認めるが、今後適応症例の検討が必要である。(著者抄録)