Publications by authors named "Junji Uchida"

165 Publications

Efficacy and safety of ramucirumab plus docetaxel in older patients with advanced non-small cell lung cancer: A multicenter retrospective cohort study.

J Geriatr Oncol 2021 Sep 30. Epub 2021 Sep 30.

Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, 1180 Nagasone-cho, Kita-Ku, Sakai City, Osaka 591-8555, Japan.

Objective: Ramucirumab (RAM) plus Docetaxel (DOC) is one of the standard treatments after first-line treatment failure in patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the efficacy and safety of RAM plus DOC in older patients. We aimed to clarify these and elucidate the prognostic factors.

Materials And Methods: In this multicenter retrospective study, conducted at four medical facilities in Japan, we evaluated the efficacy and safety data for two groups (<65 and ≥ 65 years). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and log-rank test. Multivariate analysis was performed to reveal the prognostic factors for better PFS and OS. Patient characteristics and adverse events (AEs) in both groups were compared using the Mann-Whitney's U and Fisher's exact tests for categorical variables.

Results: A total of 237 patients were included, of whom 43% (n = 103), and 57% (n = 134) were aged <65, and ≥ 65 years. Median OS was 12.2 (95% CI: 9.4-15.0), and 14.8 months (95% CI: 10.8-18.8), respectively, and there were no significant differences between the groups (p = 0.534). Multivariate analysis identified DOC dose reduction (none vs performed, HR: 2.66, 95% CI: 1.62-4.35, p < 0.001) as an independent prognostic factor for OS in older patients, and a similar result was shown for the PFS. Grade ≥ 3 all AEs were identified in 42.7% and 56.7% of younger and older patients, respectively, and there was a significant difference between the groups (p = 0.033); however, the difference between the groups disappeared with primary DOC dose reduction (p = 0.526).

Conclusion: The efficacy of RAM plus DOC administration in older, pretreated patients with advanced NSCLC was comparable to those of younger patients, whereas RAM plus DOC should be cautiously administered to older patients because of severe toxicity. Moreover, appropriate DOC dose reduction may be recommended for increased survival benefit and safety in such patients.
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http://dx.doi.org/10.1016/j.jgo.2021.09.004DOI Listing
September 2021

Drug-Induced Kidney Injury Caused by Osimertinib: Report of a Rare Case.

Nephron 2021 Sep 17:1-6. Epub 2021 Sep 17.

Department of Respiratory Medicine, Osaka General Medical Center, Osaka, Japan.

Tyrosine kinase inhibitors (TKIs) that target the epidermal growth factor receptor (EGFR) have shown highly favourable outcomes in patients with advanced-stage non-small-cell lung cancer (NSCLC). The adverse effects of EGFR-TKIs are generally less severe than those of conventional cytotoxic therapies. We report a patient with NSCLC who presented with acute kidney injury associated with biopsy-proven acute tubular injury during osimertinib treatment and whose renal function recovered after reducing the osimertinib dose. A 61-year-old male smoker complained of dyspnoea on exertion for 1 month before his visit to the medical centre. He was diagnosed with lung adenocarcinoma of the left lower lobe (cT4N3M1a, stage IVA) and was positive for an EGFR mutation (exon 19 deletion). Osimertinib was initiated at 80 mg/day. At treatment initiation, the patient's serum creatinine level was 0.64 mg/dL, with microscopic haematuria; by day 83, this level had increased to 1.33 mg/dL, with proteinuria. On day 83, we reduced the osimertinib dose to 40 mg/day and performed a kidney biopsy on day 98. The histological diagnosis was tubular injury with IgA deposition. Based on the clinical course and histological findings, we speculated that the kidney injury was associated with osimertinib. After dose reduction, the patient's serum creatinine level decreased to 1.07 mg/dL, and proteinuria disappeared. He maintained a partial response for >6 months after osimertinib administration. We report the first case of biopsy-proven mild IgA deposition, crescent formation, and tubular injury probably caused by osimertinib and demonstrate how reducing the osimertinib dose could strike a balance between its anti-cancer efficacy and adverse effects.
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http://dx.doi.org/10.1159/000518774DOI Listing
September 2021

Impact of the objective response to and number of cycles of platinum-based first-line chemotherapy for metastatic urothelial carcinoma on overall survival of patients treated with pembrolizumab.

Int J Urol 2021 Sep 20. Epub 2021 Sep 20.

Department of Urology, University of Toyama, Toyama, Japan.

Objectives: To investigate the impact of the number of cycles and objective response to chemotherapy on overall survival in patients with metastatic urothelial carcinoma treated with pembrolizumab.

Methods: This multicenter, retrospective study included 755 patients from 59 institutions with advanced, chemoresistant urothelial carcinoma who received pembrolizumab. The associations of the overall survival with the number of cycles and best objective response were investigated using Cox multiple regression analysis.

Results: Overall, 391 patients received standard first-line chemotherapy and pembrolizumab as a second-line treatment, and were included in the final analysis. Of the 391 patients, 185 received less than four cycles, 134 received four to six cycles and 72 received more than six cycles of first-line chemotherapy. An objective response (complete or partial response) to chemotherapy was observed in 145 patients (37.1%). Univariate analysis showed that the overall survival of patients who received more than six cycles or responded to chemotherapy (complete or partial response) was significantly longer than that of patients who received less than four cycles or did not respond to chemotherapy (stable or progressive disease). At multivariate levels, no correlations were observed between overall survival and the number of cycles of or the response to chemotherapy.

Conclusions: Therapeutic benefit of pembrolizumab can be expected irrespective of the objective response to and number of cycles of platinum-based first-line chemotherapy.
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http://dx.doi.org/10.1111/iju.14686DOI Listing
September 2021

Dissociation of Glycated Albumin and HbA Is Associated With a Decline of Glomerular Filtration Rate as Evaluated by Inulin Clearance.

Diabetes Care 2021 Nov 15;44(11):e188-e189. Epub 2021 Sep 15.

Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.

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http://dx.doi.org/10.2337/dc21-1218DOI Listing
November 2021

Impact of stroke history on the presence of cerebral microbleeds in hemodialysis patients.

BMC Neurol 2021 Aug 11;21(1):311. Epub 2021 Aug 11.

Department of Medical Statistics, Osaka City University, Osaka, Osaka, Japan.

Introduction: Cerebral microbleeds (CMBs) are detected on gradient-echo T2*-weighted magnetic resonance imaging (MRI). Clinically, CMBs are often detected after stroke, including in cases of intracerebral hemorrhage and ischemic cerebrovascular disease. Hemodialysis (HD) patients are widely known to have a high incidence of stroke, and HD patients without stroke history have been reported to have a high prevalence of CMBs. In this study, we investigated whether history of stroke affects the prevalence of CMBs in HD patients.

Methods: A cross-sectional study was performed in 241 HD patients who underwent brain T2*-weighted MRI. We compared the prevalence of CMBs between the patients with and without a history of stroke. Moreover, the relationship between history of stroke and presence of CMBs was examined by multivariate logistic regression analysis.

Results: Among these patients, 22 (9.1%) had a history of stroke. CMBs were detected in 70 patients (29.0%). The prevalence of CMBs was significantly higher in patients with a history of stroke compared to those without this history (54.5 vs. 26.5%, p = 0.012). In the multivariable analysis adjusted for background characteristics, history of stroke was a significant and independent factor related to CMBs (OR: 3.24, 95%CI: 1.18-8.89, p = 0.02).

Discussion/conclusions: As has been reported for non-dialysis patients, our results showed a high prevalence of CMBs in HD patients with a history of stroke, and indicated that a history of stroke is significantly and independently associated with CMBs in HD patients.
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http://dx.doi.org/10.1186/s12883-021-02320-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356420PMC
August 2021

Antiplatelet therapy and future intracerebral hemorrhage in hemodialysis patients with cerebral microbleeds.

J Clin Neurosci 2021 Aug 8;90:155-160. Epub 2021 Jun 8.

Department of Medical Statistics, Osaka City University, Osaka, Osaka, Japan.

The use of antiplatelet drugs is thought to increase the risk for intracerebral hemorrhage (ICH) in patients with cerebral microbleeds (CMBs). However, hemodialysis (HD) patients have a high prevalence of CMBs and diverse pathologies that require antiplatelet therapy. In this study, we investigated whether the use of antiplatelet drugs increases the risk for ICH in HD patients with CMBs. Brain magnetic resonance imaging (MRI), including T2*-weighted MRI, was performed in 179 HD patients with no history of cerebrovascular events. CMBs were detected and patients were followed prospectively with a median follow-up period of 5.2 [1.4-6.2] years. To investigate whether the influence of antiplatelet therapy on the development of ICH differs in cases with and without CMBs, the inverse probability of treatment weighting method was used, including an interaction term between the presence or absence of CMBs and use of antiplatelet drugs. As a result, CMBs were detected in 45 patients (25.1%), and antiplatelet drugs were used in 66 patients (36.9%). When the effect of antiplatelet therapy on the incidence of ICH was modified by the presence of CMBs at baseline (P for interaction <0.001), the use of antiplatelet drugs was a significant risk factor for ICH in HD patients without CMBs, but not in HD patients with CMBs. Furthermore, the burden of CMBs significantly increased the risk for ICH, but the increase in this risk was slower in antiplatelet drug users as compared to non-antiplatelet drug users (P for interaction = 0.02). The influence of antiplatelet drugs on the development of ICH differed depending on the presence or absence of CMBs. In fact, the use of antiplatelet drugs did not increase the risk for ICH in HD patients with CMBs.
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http://dx.doi.org/10.1016/j.jocn.2021.05.068DOI Listing
August 2021

A case of primary retroperitoneal amyloidoma resected laparoscopically.

Urol Case Rep 2021 Sep 13;38:101711. Epub 2021 May 13.

Department of Urology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.

Amyloidosis is known as a group of diseases that causes various disorders because of deposition of amyloid protein in various organs. Amyloidosis occurring in the retroperitoneum is a rare disease. We report a 75-year-old male patient presented to our hospital because he was identified with a retroperitoneal mass incidentally by CT. Laparoscopic surgery was performed to resect the tumor. In the histopathological specimen, amyloid was found in the fibrous soft tissue by Congo red staining. This is the first report to document a primary solitary amyloidosis of the retroperitoneum without systemic amyloidosis, which was resected using the laparoscopic approach.
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http://dx.doi.org/10.1016/j.eucr.2021.101711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141888PMC
September 2021

Intensity-modulated radiation therapy with concurrent chemotherapy followed by durvalumab for stage III non-small cell lung cancer: A multi-center retrospective study.

Radiother Oncol 2021 07 21;160:266-272. Epub 2021 May 21.

Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background And Purpose: Intensity-modulated radiation therapy (IMRT) is increasingly applied in concurrent chemoradiotherapy (CCRT) for locally-advanced non-small cell lung cancer (NSCLC), with improvement of target coverage and better sparing of normal tissue. IMRT tends to have a larger low-dose irradiation volume than 3D conformal radiotherapy, but the incidence of and risk factors for pneumonitis remain unclear, especially following the approval of durvalumab.

Materials And Methods: We retrospectively reviewed the records of NSCLC patients treated by CCRT using IMRT at seven Japanese institutions. Primary outcomes were incidence of symptomatic pneumonitis and progression-free survival (PFS). Multivariate logistic regression analysis was used to identify risk factors for ≥grade 2 pneumonitis.

Results: Median follow-up from the start of CCRT was 14.3 months (n = 107 patients; median age 70 years, 29% female). Median lung V5 and V20 was 49.2% and 19.5%, respectively. Durvalumab was administered to 87 patients (81%). Pneumonitis developed in 95 (89%) patients of which 53% had grade 1, 28% grade 2, 6.5% grade 3, and 0.9% grade 4. Durvalumab had been discontinued in 16 patients (18.4%) due to pneumonitis. By multivariate analysis, age ≥70 years, male sex, and V5 ≥58.9% were identified as significantly associated with ≥grade 2 pneumonitis (p = 0.0065, 0.036 and 0.0013 respectively). The median PFS from the start of CCRT was not reached (95% CI, 14.2 months to not reached) in patients receiving durvalumab.

Conclusion: CCRT using IMRT followed by durvalumab was generally effective and tolerable; V5 <60% would be recommended to avoid symptomatic pneumonitis.
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http://dx.doi.org/10.1016/j.radonc.2021.05.016DOI Listing
July 2021

Impact of docetaxel plus ramucirumab on metastatic site in previously treated patients with non-small cell lung cancer: a multicenter retrospective study.

Transl Lung Cancer Res 2021 Apr;10(4):1642-1652

Department of Respiratory Medicine, Osaka Prefectural Medical Center for Respiratory and Allergic Disease, Osaka, Japan.

Background: Docetaxel (DOC) plus ramucirumab (RAM) has been recommended as an optimal therapy for previously treated patients with non-small cell lung cancer (NSCLC). In a clinical setting, there are few reports about DOC plus RAM, therefore its effect on factors such as Eastern Cooperative Oncology Group (ECOG) performance status (PS) and metastatic sites is still unknown.

Methods: We recruited NSCLC patients who received DOC plus RAM in four medical facilities in Japan from June 2016 to March 2020. We retrospectively investigated the overall response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) of DOC plus RAM and conducted univariate and multivariate analyses using PFS as a dependent factor. Patients were followed up until June 30, 2020.

Results: A total of 237 patients were consecutively enrolled. For all patients, the ORR, DCR, and median PFS were 25.2%, 63.9%, and 4.5 months, respectively. The ORR and DCR for malignant pleural effusion (MPE), lung metastasis, and liver metastasis were 7.7% and 53.8%, 30.3% and 77.5%, and 48.6% and 71.4%, respectively. In the multivariate analysis, MPE, lung metastasis, and liver metastasis were not prognostic factors for poor PFS. However, ECOG-PS 2 or more [hazard ratio (HR): 1.66, 95% confidence interval (CI): 1.14-2.40, P=0.008] and brain metastasis (HR: 1.71, 95% CI: 1.23-2.37, P=0.001) were significant and independent factors associated with shorter PFS.

Conclusions: DOC plus RAM could be an optimal therapy for previous treated NSCLC patients with lung and liver metastasis, and furthermore, should be used carefully for patients with poor ECOG-PS or brain metastasis.

Keywords: Docetaxel and ramucirumab; non-small cell lung cancer (NSCLC); metastatic site; poor performance status.
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http://dx.doi.org/10.21037/tlcr-20-1263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8107751PMC
April 2021

Clinical factors associated with shorter durable response, and patterns of acquired resistance to first-line pembrolizumab monotherapy in PD-L1-positive non-small-cell lung cancer patients: a retrospective multicenter study.

BMC Cancer 2021 Apr 1;21(1):346. Epub 2021 Apr 1.

Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, 541-8567, Japan.

Background: Despite the wide-spread use of immune checkpoint inhibitors (ICIs) in cancer chemotherapy, reports on patients developing acquired resistance (AR) to ICI therapy are scarce. Therefore, we first investigated the characteristics associated with shorter durable responses of ICI treatment and revealed the clinical patterns of AR and prognosis of the patients involved.

Methods: We conducted a retrospective multi-center cohort study that included NSCLC patients with PD-L1 tumor proportion scores of ≥50% who received first-line pembrolizumab and showed response to the therapy. Among patients showing response, progression-free survival (PFS) was investigated based on different clinically relevant factors. AR was defined as disease progression after partial or complete response based on Response Evaluation Criteria in Solid Tumors. Among patients with AR, patterns of AR and post-progression survival (PPS) were investigated. Oligoprogression was defined as disease progression in up to 5 individual progressive lesions.

Results: Among 174 patients who received first-line pembrolizumab, 88 showed response and were included in the study. Among these patients, 46 (52%) developed AR. Patients with old age, poor performance status (PS), at least 3 metastatic organs, or bone metastasis showed significantly shorter PFS. Among 46 patients with AR, 32 (70%) developed AR as oligoprogression and showed significantly longer PPS than those with non-oligoprogressive AR.

Conclusions: Patients with old age, poor PS, at least 3 metastatic organs, or bone metastasis showed shorter durable responses to pembrolizumab monotherapy. Oligoprogressive AR was relatively common and associated with better prognosis. Further research is required to develop optimal approaches for the treatment of these patients.
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http://dx.doi.org/10.1186/s12885-021-08048-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017679PMC
April 2021

Safety and Efficacy of Tandem Hemodialysis and Selective Plasma Exchange in Pretransplant Desensitization of ABO-Incompatible Kidney Transplantation.

Blood Purif 2021 21;50(6):829-836. Epub 2021 Jan 21.

Department of Medical Statistics, Osaka City University, Osaka, Japan.

Introduction: In patients requiring both hemodialysis (HD) and apheresis, the 2 treatments can be performed simultaneously. At our hospital, selective plasma exchange (SePE) is often performed along with HD for removal of isoagglutinins before ABO-incompatible (ABOi) kidney transplantation. The 2 treatments can be completed within the HD schedule, which allows the treatment time to be shortened. This approach is also less stressful for patients because fewer punctures are required. In this study, we investigated the safety and efficacy of tandem HD and SePE.

Methods: A total of 58 SePE sessions in 30 ABOi kidney transplant recipients were investigated. The SePE circuit was connected in parallel with the HD circuit, and tandem HD and SePE therapy was performed using filtration methods. The SePE sessions were divided into 2 groups: those with SePE monotherapy (group S, n = 20) and those with tandem therapy (group T, n = 38). Changes in transmembrane pressure (TMP), arterial pressure (AP), venous pressure (VP), and decrease in isoagglutinin titers over time were compared between the groups with adjustment for background data.

Results: The internal pressures (AP and VP) were higher in group T, and there were significant differences in changes of TMP and AP over time between groups T and S. Membrane exchange was required in 1 case in group T due to coagulation. There was a more significant decrease of immunoglobulin G isoagglutinin titers in group T compared to group S. No case had antibody-mediated rejection after transplantation.

Discussion/conclusion: In HD/SePE tandem therapy, internal pressures were higher and TMP and AP tended to increase more compared to SePE monotherapy, but we were able to perform the 2 treatments without any functional problems. Tandem therapy was also effective in decreasing isoagglutinin titers, which suggests that this may be a beneficial treatment modality as apheresis before ABOi kidney transplantation.
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http://dx.doi.org/10.1159/000512713DOI Listing
January 2021

Durvalumab for patients with unresectable stage III non-small cell lung cancer and grade 1 radiation pneumonitis following concurrent chemoradiotherapy: a multicenter prospective cohort study.

Invest New Drugs 2021 06 6;39(3):853-859. Epub 2021 Jan 6.

Internal Medicine III, Wakayama Medical University, 811-1, Kimiidera, Wakayama, Wakayama, Japan.

Introduction/Background Durvalumab demonstrated a good efficacy and safety in patients with unresectable stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CCRT) in the PACIFIC trial. Although a history of radiation pneumonitis (RP) has been reported to increase the risk of pneumonitis associated with programmed death-1 inhibitors, the safety and efficacy of durvalumab in patients with baseline Grade 1 RP have not been assessed. Therefore, we carried out a multicenter prospective cohort study to evaluate the efficacy and safety of durvalumab in these patients. Patients and Methods This was a multicenter prospective cohort study of 35 patients with Grade 1 RP after CCRT and before durvalumab initiation. This study was a first prespecified analysis for the first 20 patients with the primary objective of assessing the short-term safety; it was assessed 3 months after durvalumab initiation. Results Twenty patients were enrolled in this study between March 1, 2019, and September 3, 2019. Three patients (15%) experienced drug-related Grade ≥3 adverse events, while three patients (15%) had Grade ≥2 pneumonitis/RP within 3 months after durvalumab initiation. Three months after durvalumab initiation, all the patients were alive and four patients (20%) experienced disease progression. Conclusion Durvalumab can be a feasible treatment option for patients with stage III NSCLC with baseline Grade 1 RP following CCRT.(Trial registration number: UMIN000036061. The registration period was between March 2019 and December 2019.).
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http://dx.doi.org/10.1007/s10637-020-01060-8DOI Listing
June 2021

A case of anti-aquaporin-4 antibody-positive optic neuritis treated by selective immunoadsorption.

Transfus Apher Sci 2021 Feb 20;60(1):102969. Epub 2020 Oct 20.

Department of Urology, Osaka City University, Osaka, Japan.

Anti-aquaporin-4 (AQP4) antibody-positive optic neuritis is a condition in which a patient testing positive for anti-AQP4 antibody presents with optic neuritis only. The disease is classified as a neuromyelitis optica spectrum disorder (NMOSD) and is a steroid-resistant refractory optic neuritis. Patients are treated by oral administration of steroids, steroid pulse therapy, and apheresis therapy. The patient in our case was a 48-year-old female who was diagnosed with anti-AQP4 antibody-positive optic neuritis by her ophthalmologist, and was referred to our hospital. Selective plasma exchange (SePE) was initially started, but she strongly preferred treatment as an outpatient due to family circumstances. Therefore, selective immunoadsorption (SeIA) was used from the second session to minimize loss of coagulation factors. The RRs were 16.5-33.3% for anti-AQP4 antibody, 7.48-18.57% for fibrinogen, and 0.8-4.57% for factor XIII. After the 7th SeIA session, the patient was followed up with a maintenance dose of 10 mg/day oral prednisolone as an outpatient at our Department of Ophthalmology. This is the first report to investigate the removal rate (RR) of anti-AQ4 antibody using SeIA. In our case, the anti-AQP4 antibody level before the last SeIA session was still not completely negative, but there was clinical improvement in vision. SeIA was highly effective in maintaining coagulation factor levels. Therefore, our results suggest that SeIA is a safe treatment that can be performed in an outpatient setting.
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http://dx.doi.org/10.1016/j.transci.2020.102969DOI Listing
February 2021

Increased Glomerular Hydrostatic Pressure is Associated with Tubular Creatinine Reabsorption in Healthy Subjects.

Kidney Blood Press Res 2020 5;45(6):996-1008. Epub 2020 Nov 5.

Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.

Background: Cr is secreted by the proximal tubules and thus Cr clearance (Ccr) can overestimate inulin clearance (Cin). However, in some cases, Ccr can even underestimate Cin. This suggests that Cr could be reabsorbed in the tubuli. We examined the clinical parameters that are associated with tubular Cr reabsorption.

Methods: In 80 kidney donor candidates (53.9 ± 13.2 years, 29 males), Cin and para-aminohippuric acid clearance were measured simultaneously. Intrarenal hemodynamic parameters were calculated by Gomez's formulae. To quantify the secretory component of Ccr (SFcr), it was calculated as follows: SFcr = (Ccr - Cin)/Ccr.

Results: Twenty-five subjects (31.3%) showed SFcr values <0. SFcr that correlated significantly and negatively with efferent arteriolar resistance (Re) and glomerular hydrostatic pressure (Pglo) (Re: r = -0.30, p = 0.008; Pglo: r = -0.28, p = 0.025). In multiple regression analyses, Re and Pglo were significantly and negatively associated with SFcr after adjustment for other confounders.

Conclusions: These findings suggest that tubular reabsorption of Cr can occur in some cases. Intrarenal glomerular hemodynamic burden may be related to tubular creatinine reabsorption, which possibly leads to lower Ccr values.
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http://dx.doi.org/10.1159/000510838DOI Listing
May 2021

A case of simultaneous occurrence of hepatitis and pancreatitis during the combination immunochemotherapy for non-small cell lung carcinoma.

Respir Med Case Rep 2020 20;31:101266. Epub 2020 Oct 20.

Department of Respiratory Medicine, Osaka General Medical Center, Osaka, Japan.

Immune checkpoint inhibitors (ICIs) improved the prognosis of patients with advanced lung cancers. The combination therapy of cytotoxic drugs and ICI is approved as first-line chemotherapy in non-small-cell lung cancer (NSCLC) and extensive disease small-cell lung cancer (ED-SCLC). It has been reported various immune-related adverse events (irAEs). We herein report a 65-year-old man with NSCLC who developed hepatitis and pancreatitis simultaneously during the combination immunochemotherapy. In the treatment of hepatitis and pancreatitis, the clinical course was different. In this report, the importance of accurate diagnosis through detailed examination and treatment priority depending on the severity of the symptoms is indicated.
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http://dx.doi.org/10.1016/j.rmcr.2020.101266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7589533PMC
October 2020

Pilot experience of simultaneous robotic-assisted partial nephrectomy for bilateral renal tumors-single center analysis.

Asian J Endosc Surg 2021 Jan 29;14(1):57-62. Epub 2020 Jun 29.

Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Introduction: Bilateral renal tumors accounts for approximately 3% of renal tumors. However, surgical treatment methods for bilateral renal tumors have not yet been established. It is imperative to balance the need for curative surgery with the goal of maximal functional preservation in patients with bilateral synchronous renal tumors. Therefore, partial nephrectomy may be the optimal surgical treatment for bilateral synchronous renal tumors.

Methods: We conducted a retrospective, observational study to analyze the clinical outcome of simultaneous robotic-assisted partial nephrectomy (RAPN) for bilateral renal tumors at our institution between 2016 and 2019. A total of eight patients were enrolled and the number of renal masses in the 16 kidneys was 18.

Results: There was no positive surgical margin after RAPN in our case series and no local recurrence or metastasis during the follow-up period. The only complication of simultaneous RAPN in the present case series was that one patient experienced acute kidney injury after operation without need for dialysis therapy.

Conclusion: Our study suggests that simultaneous RAPN for bilateral renal tumors might be feasible both for the preservation of renal function and for oncological outcome such as negative surgical margin.
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http://dx.doi.org/10.1111/ases.12831DOI Listing
January 2021

ABO-Incompatible Kidney Transplantation After Bone Marrow Transplantation: A Case Report.

Transplant Proc 2020 Nov 23;52(9):2754-2757. Epub 2020 Jun 23.

Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Many studies have been made on ABO-compatible kidney transplants following hematopoietic stem cell transplantation. However, there have been few reports on ABO-incompatible kidney transplantation following hematopoietic stem cell transplantation (HSCT). We report on the case of a successful ABO-incompatible kidney transplantation with high titers after bone marrow transplantation experienced no infectious episodes. The patient was a 38-year-old man with end-stage kidney disease resulting from interstitial nephritis induced by drug toxicity or graft-vs-host disease (GVHD). He had received allogeneic bone marrow transplantation from a human leukocyte antigen-identical unrelated donor to treat chronic myelogenous leukemia. The patient with high anti-B antibody titers (IgM 1:1024 IgG 1:256) received a desensitization protocol consisting of 2 doses of rituximab and 5 courses of plasmapheresis. The patient had prolonged depletion of circulating B cells 2 years after the transplant and was infected with cytomegalovirus viremia, pneumocystis jiroveci pneumonia, and adenovirus urinary tract infection at 2, 3, and 17 months post-transplant, respectively. Currently, at 6 years after his transplant, the patient has had no rejection and is in good clinical condition with only mild renal insufficiency. Our results suggest that ABO-incompatible kidney transplantation may be an effective renal replacement therapy for patients with end-stage kidney disease after HSCT, but desensitization in combination with immunosuppressants could lead to a state of over-immunosuppression, causing various infections.
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http://dx.doi.org/10.1016/j.transproceed.2020.01.173DOI Listing
November 2020

Splenectomy for ABO-Incompatible Kidney Transplantation and Very Late-Onset Cytomegalovirus Disease.

Urol Int 2020 19;104(7-8):651-656. Epub 2020 May 19.

Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Introduction: Splenectomy had been previously performed in ABO-incompatible kidney transplantation to reduce the B cell pool. However, studies have shown that patients undergoing splenectomy may have a lifelong susceptibility to infection and mortality. Splenectomy may affect the incidence of cytomegalovirus (CMV) disease even at a very late stage after transplantation in ABO-incompatible recipients.

Patients And Methods: Seven patients received their graft from an ABO-incompatible living donor at our institution and underwent splenectomy for B cell reduction. Among them, 3 recipients experienced very late-onset CMV disease approximately 10 years after their transplant and were enrolled in this study.

Results: Very late-onset CMV disease occurred at 9 years and 9 months, 15 years, and 13 years and 5 months after transplantation, respectively. Two recipients suffered from CMV retinitis, while one experienced colitis. The age of the patients at onset of CMV disease was 69 years, 42 years, and 71 years, respectively.

Conclusion: This may be the first report on very late-onset CMV disease after splenectomy in ABO-incompatible kidney transplantation. We should be aware that these recipients can experience very late-onset CMV disease even approximately 10 years after their transplant.
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http://dx.doi.org/10.1159/000504862DOI Listing
April 2021

Acquired resistance to trastuzumab/pertuzumab or to T-DM1 in vivo can be overcome by HER2 kinase inhibition with TAS0728.

Cancer Sci 2020 Jun 30;111(6):2123-2131. Epub 2020 Apr 30.

Discovery and Preclinical Research Division, Taiho Pharmaceutical Co., Ltd., Tsukuba, Japan.

HER2-targeting antibodies (trastuzumab, pertuzumab) and a HER2-directed antibody-drug conjugate (trastuzumab emtansine: T-DM1) are used for the treatment of HER2-overexpressing breast cancer. However, these treatments eventually become ineffective due to acquired resistance and there is an urgent need for alternative therapies. TAS0728 is a small-molecule, irreversible selective HER2 kinase inhibitor. In the present study, we established new in vivo models of cancer resistance by continuous exposure to a combination of trastuzumab and pertuzumab or to T-DM1 for evaluating the effect of TAS0728 on HER2 antibody-resistant populations. Treatment with trastuzumab and pertuzumab or with T-DM1 initially induced tumor regression in NCI-N87 xenografts. However, tumor regrowth during treatment indicated loss of drug effectiveness. In tumors with acquired resistance to trastuzumab and pertuzumab or to T-DM1, HER2-HER3 phosphorylation was retained. Switching to TAS0728 resulted in a significant anti-tumor effect associated with HER2-HER3 signal inhibition. No alternative receptor tyrosine kinase activation was observed in these resistant tumors. Furthermore, in a patient-derived xenograft model derived from breast cancer refractory to both trastuzumab/pertuzumab and T-DM1, TAS0728 exerted a potent anti-tumor effect. These results suggest that tumors with acquired resistance to trastuzumab and pertuzumab and to T-DM1 are still dependent on oncogenic HER2-HER3 signaling and are vulnerable to HER2 signal inhibition by TAS0728. These results provide a rationale for TAS0728 therapy for breast cancers that are refractory to established anti-HER2 therapies.
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http://dx.doi.org/10.1111/cas.14407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293079PMC
June 2020

Prolyl-hydroxylase inhibitors reconstitute tumor blood vessels in mice.

J Pharmacol Sci 2020 Jun 3;143(2):122-126. Epub 2020 Mar 3.

Department of Pharmacology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan. Electronic address:

Tumor blood vessels have leaky and low blood flow properties, which lead to hypoxia and low nutrient levels in the tumor tissue area known as the tumor microenvironment (TME). We reported that the prolyl-hydroxylase (PHD) inhibitor Roxadustat normalized tumor blood vessels, improved tumor tissue perfusion, and re-oxygenated the tumor tissue. Recently, several PHD inhibitors including Roxadustat, Daprodustat, Molidustat, and Vadadustat, were evaluated in clinical trials and approved for treating renal anemia. In this study, we showed that PHD inhibitors reconstituted tumor blood vessels and improved the TME, and some agents exhibited differential effects on tumors in a mouse model.
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http://dx.doi.org/10.1016/j.jphs.2020.02.010DOI Listing
June 2020

Frailty is associated with dialysis duration before transplantation in kidney transplant recipients: A Japanese single-center cross-sectional study.

Int J Urol 2020 May 7;27(5):408-414. Epub 2020 Mar 7.

Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Objectives: To investigate the prevalence of frailty, and the relationship of frailty based on the Kihon Checklist criteria with dialysis duration before transplantation and time after transplantation in kidney transplant recipients.

Methods: This study was a single-center, cross-sectional investigation carried out on kidney transplant recipients. To examine the association between the total Kihon Checklist score with time after transplant and dialysis duration before transplant, the multivariable proportional odds logistic regression model was used with adjustment for age, sex, body mass index, estimated glomerular filtration rate and serum albumin levels.

Results: Out of 205 kidney transplant recipients enrolled in this study, frail, prefrail and robust recipients accounted for 11.2%, 26.8% and 62.0%, respectively. Dialysis duration before transplantation was associated with frailty, but time after transplant was not associated with frailty.

Conclusions: The prevalence of frailty in kidney transplant recipients is approximately 11%, and it is associated with the duration of pretransplant dialysis. These findings suggest that a shorter dialysis duration might be beneficial for preventing frailty in kidney transplant recipients.
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http://dx.doi.org/10.1111/iju.14208DOI Listing
May 2020

Association Between Early Immune-related Adverse Events and Clinical Outcomes in Patients With Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.

Clin Lung Cancer 2020 07 4;21(4):e315-e328. Epub 2020 Feb 4.

Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.

Introduction: Previous studies have described an association between immune-related adverse events (irAEs) and better outcomes in patients administered nivolumab for advanced non-small-cell lung cancer. However, the patients in previous studies were not stratified by potential predictive factors, such as programmed cell death ligand 1 status and treatment lines. Additionally, little is known of whether the timing and type of irAEs can inform the prediction of outcomes.

Patients And Methods: We prospectively investigated the association between irAEs and outcomes in the single-center cohort that included patients administered nivolumab in the second or later line of therapy. Subsequently, we confirmed these findings in a retrospective multicenter cohort that included patients with programmed cell death ligand 1 tumor proportion score of ≥ 50% who had received first-line pembrolizumab. The primary outcome was progression-free survival (PFS).

Results: In the prospective cohort (n = 76), the median PFS was significantly longer for the patients experiencing irAEs within 2 weeks of beginning nivolumab compared with the PFS for those who did not (median, 5.0 months [95% confidence interval (CI), 2.1-8.6 months] vs. median, 2.0 months [95% CI, 1.9-2.5 months]; P = .046). The association was stronger with earlier (within 2 weeks) than with later (within 6 weeks) irAEs. In the retrospective cohort (n = 148), the median PFS was significantly longer for the patients with early irAEs (within 3 weeks) than for those without (median, not reached [95% CI, 5.9 months to not reached] vs. median, 6.9 months [95% CI, 4.2-9.7 months]; P = .04). Rash was common and a better predictor of outcomes in both cohorts.

Conclusion: Our results have provided firmer evidence of the association between the occurrence of irAEs and outcomes and suggest that early irAEs (especially rash) might better predict outcomes.
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http://dx.doi.org/10.1016/j.cllc.2020.01.003DOI Listing
July 2020

Prediction of patients with a tumor proportion score > 50% who do not respond to first-line monotherapy with pembrolizumab.

BMC Cancer 2020 Feb 3;20(1):93. Epub 2020 Feb 3.

Department of Respiratory Medicine, Kobe City Medical Center West Hospital, 2-4, Ichiban-cho, Nagata-ku, Kobe-shi, Hyogo, 653-0013, Japan.

Background: Pembrolizumab is effective as first-line therapy against advanced non-small cell lung cancer (NSCLC) in patients with programmed death ligand-1 (PD-L1) expression levels ≥50% [1]. However, it is not effective in all patients, and the factors predicting responses among this population remain unknown.

Methods: We retrospectively analyzed patients with NSCLC and a PD-L1 tumor proportion score (TPS) > 50%, who received first-line monotherapy with pembrolizumab from February 1, 2017 to April 30, 2018. The study included 11 hospitals, which participated in the Hanshin Oncology clinical Problem Evaluation group (HOPE). We analyzed the differences between responders and non-responders in terms of age, sex, performance status score, degree of progression, histological type, smoking history, expression of PD-L1, use of steroids prior to treatment, metastasis site, and laboratory data.

Results: A total of 205 patients were included in this study. Of those, 108 patients exhibiting complete or partial response were defined as responders. Those exhibiting progressive disease (N = 52) were defined as non-responders. In the univariate analysis, Eastern Cooperative Oncology Group performance status score ≥ 2 (p = 0.0832), stage IV disease or recurrence (p = 0.0487), PD-L1 TPS 50-89% (p = 0.0657), use of steroids prior to the administration of pembrolizumab (p = 0.0243), malignant pleural effusion (p = 0.0032), and baseline C-reactive protein (CRP) levels > 1.0 mg/dL (p = 0.0390) were significantly associated with non-response to treatment. In the multivariate analysis, use of steroids prior to the administration of pembrolizumab (odds ratio [OR]: 5.86; 95% confidence interval [CI]: 1.32-31.8; p = 0.0200), malignant pleural effusion (OR: 2.68; 95% CI: 1.15-6.35; p = 0.0228), and baseline CRP > 1.0 mg/dL (OR: 2.17; 95% CI: 1.03-4.68; p = 0.0402) were significantly associated with non-response to treatment.

Conclusion: In real-world patients with NSCLC and a PD-L1 TPS ≥50%, use of steroids prior to treatment, malignant pleural effusion, and baseline CRP levels > 1.0 mg/dL reduced the response of first-line monotherapy with pembrolizumab.
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http://dx.doi.org/10.1186/s12885-020-6582-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6998183PMC
February 2020

Selective plasma exchange in ABO-incompatible kidney transplantation: comparison of substitution with albumin and partial substitution with fresh frozen plasma.

Sci Rep 2020 01 29;10(1):1434. Epub 2020 Jan 29.

Department of Medical Statistics, Osaka City University Graduate School of Medicine, Osaka, Japan.

We have performed selective plasma exchange (SePE) as apheresis before ABO-incompatible kidney transplantation since 2015. In this study, we divided the SePE sessions into two groups, those using albumin alone (Group A) and those partially using fresh frozen plasma (FFP) (Group F), and compared their clinical efficacies. A total of 58 sessions of SePE (Group A: n = 41, Group F: n = 17) were performed in 30 recipients of ABOi kidney transplantation during the study period and the decrease in isoagglutinin titers, changes in the levels of serum IgG and IgM as well as coagulation factors (fibrinogen, factor XIII), and incidence of side effects were retrospectively compared. There was a more significant decrease of isoagglutinin titers in Group F compared to Group A. Immunoglobulins and coagulants were replenished in Group F. Meanwhile, the incidence of side effects was significantly higher in Group F. SePE using FFP, which can effectively decrease isoagglutinins titers and replenish immunoglobulin and coagulation factors, may be a beneficial treatment modality as apheresis before ABO-incompatible kidney transplantation, in spite of a disadvantage that there are many side effects.
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http://dx.doi.org/10.1038/s41598-020-58436-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989510PMC
January 2020

Association of sarcopenia with phase angle and body mass index in kidney transplant recipients.

Sci Rep 2020 01 14;10(1):266. Epub 2020 Jan 14.

Osaka City University Graduate School of Medicine, Department of Urology, Osaka, 545-8585, Japan.

Malnutrition is an important risk factor for the development of sarcopenia. Recently, phase angle (PhA) obtained from the bioelectrical impedance analysis is increasingly becoming known as a nutritional status marker and may be considered a good indicator to identify elderly patients at risk of sarcopenia. In this study, we investigated the prevalence of sarcopenia and the relationship between sarcopenia and PhA or body mass index (BMI) as nutritional factors, and evaluated the discrimination performance of these nutritional factors for sarcopenia in 210 kidney transplant recipients. The median age was 55 years and 11.1% had sarcopenia. This prevalence of sarcopenia was lower than previous reports in kidney transplant recipients, maybe because of the differences in sarcopenia definitions and population demographics such as age, sex, race, and comorbidities. Both PhA and BMI were negatively correlated with sarcopenia after adjusting for age, sex, dialysis vintage, time after transplant, presence of diabetes mellitus, hemoglobin, estimated glomerular filtration rate, and the other nutritional factor. The discrimination performance for PhA and BMI had enough power to detect sarcopenia. These results suggest that PhA and BMI can be used in clinical practice to predict sarcopenia in kidney transplant patients.
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http://dx.doi.org/10.1038/s41598-019-57195-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959331PMC
January 2020

Effects of orally active hypoxia inducible factor alpha prolyl hydroxylase inhibitor, FG4592 on renal fibrogenic potential in mouse unilateral ureteral obstruction model.

J Pharmacol Sci 2020 Mar 6;142(3):93-100. Epub 2019 Dec 6.

Department of Applied Pharmacology and Therapeutics, Osaka City University Graduate School of Medicine, Asahimachi, Abeno-ku, Osaka, 545-8585, Japan; Ishikiri Seiki Hospital, Yayoi-cho, Higashiosaka, Osaka, 579-8026, Japan; Department of Pharmacology, Osaka City University Graduate School of Medicine, Asahimachi, Abeno-ku, Osaka, 545-8585, Japan. Electronic address:

Orally active hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors that stabilize HIF protein and stimulate the production of erythropoietin have been approved to treat renal anemia. Our previous report suggested that HIF-1α dependent fibrogenic mechanisms are operating at the early onset of renal fibrosis and its contribution declines with the progression in mouse unilateral ureteral obstruction (UUO) model. The aim of the study is to evaluate the renal fibrogenic potential of FG4592, a recently approved orally active HIF prolyl hydroxylase inhibitor in mouse UUO model. Male C57BL/6J mice orally given FG-4592 (12.5 mg/kg/day and 50 mg/kg/day) were subjected to UUO. Neither dose of FG-4592 affected renal fibrosis or macrophage infiltration. FG-4592 had no effects on increased mRNA of collagen I, collagen III or transforming growth factor-β1. At 3 days after UUO, higher dose of FG-4592 potentiated the increased mRNA expression of profibrogenic molecules, plasminogen activator inhibitor 1 (Pai-1) and connective tissue growth factor (Ctgf) but such potentiation disappeared at 7 days after UUO. It is suggested that FG-4592 used in the present study had little effects on renal fibrosis even though high dose of FG-4592 used in the present study transiently potentiated gene expression of Pai-1 and Ctgf in the UUO kidney.
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http://dx.doi.org/10.1016/j.jphs.2019.12.002DOI Listing
March 2020

Association between metastatic sites and first-line pembrolizumab treatment outcome for advanced non-small cell lung cancer with high PD-L1 expression: a retrospective multicenter cohort study.

Invest New Drugs 2020 02 30;38(1):211-218. Epub 2019 Nov 30.

Department of Thoracic Oncology, Osaka International Cancer Institute, 3-1-69 Otemachi, Osaka, 541-8567, Japan.

Associations between treatment outcomes of immune checkpoint inhibitors and metastatic sites in advanced non-small cell lung cancer (NSCLC) are not well known. Therefore, this multicenter retrospective study aimed to investigate the predictive factors of metastatic sites after first-line pembrolizumab treatment for advanced NSCLC with a PD-L1 tumor proportion score (TPS) ≥50%. We retrospectively analyzed advanced NSCLC patients with a PD-L1 TPS ≥50% who underwent first-line pembrolizumab therapy at 11 institutions between February 2017 and April 2018. Clinical data collected from medical records included metastatic sites at the time of pembrolizumab treatment. Treatment outcomes of pembrolizumab were assessed according to the Response Evaluation Criteria in Solid Tumors, version 1.1. In total, 213 patients were included in the study. The median age was 71 years (range 39-91 years). Of the 213 patients, 176 (83%) were men and 172 (81%) had an Eastern Cooperative Oncology Group performance status (ECOG-PS) score of 0-1. The most common metastases were thoracic lymph node metastasis (77%), intrapulmonary metastasis (31%), bone metastasis (28%), and malignant pleural effusion (26%). On multivariate analysis, a poor ECOG-PS score (hazard ratio: 1.95, 95.0% confidence interval: 1.25-3.04; P = 0.003) and malignant pleural effusion (hazard ratio: 1.52, 95.0% confidence interval: 1.01-2.29; P = 0.043) were independent predictors of shorter progression-free survival in patients treated with pembrolizumab. For NSCLC patients with malignant pleural effusion, pembrolizumab monotherapy is not a suitable first-line treatment because of its insufficient effectiveness, even though their PD-L1 TPS was high.
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http://dx.doi.org/10.1007/s10637-019-00882-5DOI Listing
February 2020

Delayed Neurologic Sequelae Caused By Carbon Monoxide Poisoning in a Kidney Transplant Recipient.

Exp Clin Transplant 2019 12 11;17(6):849-851. Epub 2019 Oct 11.

From the Deparment of Urology and Osaka City University Graduate School of Medicine, Osaka, Japan.

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http://dx.doi.org/10.6002/ect.2019.0034DOI Listing
December 2019

Latest insights on ABO-incompatible living-donor renal transplantation.

Int J Urol 2020 Jan 14;27(1):30-38. Epub 2019 Sep 14.

Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.

This review summarizes the latest insights on ABO-incompatible living-donor renal transplantation. Desensitization protocols and clinical outcomes were investigated, and a comparison was made with kidney-paired donation, which is not permitted in Japan for ethical reasons. Although renal transplantation is greatly beneficial for most patients with end-stage kidney disease, many of these patients must remain on dialysis therapy for extended periods due to the scarcity of organs from deceased donors. ABO blood type incompatibility was once believed to be a contraindication to renal transplantation due to the increased risk for antibody-mediated rejection and early graft loss attributable to isoagglutinins. Recently, pretransplant desensitization strategies, such as removal of isoagglutinins and antibody-producing cells, have achieved successful outcomes, although it remains unclear whether graft survival and patient morbidity are equivalent to those for ABO-compatible renal transplantation. The present review suggested that ABO-incompatible living-donor renal transplantation might be a favorable radical renal replacement therapy for patients with end-stage kidney disease.
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http://dx.doi.org/10.1111/iju.14109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004137PMC
January 2020
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