Kengo Imanishi

Effect of an Oral Adsorbent, AST-120, on Dialysis Initiation and Survival in Patients with Chronic Kidney Disease

The oral adsorbent AST-120 has the potential to delay dialysis initiation and improve survival of patients on dialysis. We evaluated the effect of AST-120 on dialysis initiation and its potential to improve survival in patients with chronic kidney disease. The present retrospective pair-matched study included 560 patients, grouped according to whether or not they received AST-120 before dialysis (AST-120 and non-AST-120 groups). The cumulative dialysis initiation free rate and survival rate were compared by the Kaplan-Meier method. Multivariate analysis was used to determine the impact of AST-120 on dialysis initiation. Our results showed significant differences in the 12- and 24-month dialysis initiation free rate (P < 0.001), although no significant difference was observed in the survival rate between the two groups. In conclusion, AST-120 delays dialysis initiation in chronic kidney disease (CKD) patients but has no effect on survival. AST-120 is an effective therapy for delaying the progression of CKD.

Skin perfusion pressure is a prognostic factor in hemodialysis patients.

Peripheral arterial disease (PAD) is common in hemodialysis patients and predicts a poor prognosis. We conducted a prospective cohort study to identify risk factors for PAD including skin perfusion pressure (SPP) in hemodialysis patients. The cohort included 373 hemodialysis patients among 548 patients who received hemodialysis at Oyokyo Kidney Research Institute, Hirosaki, Japan from August 2008 to December 2010. The endpoints were lower limb survival (peripheral angioplasty or amputation events) and overall survival of 2 years. Our results showed that <70 mmHg SPP was a poor prognosis for the lower limb survival and overall survival. We also identified age, history of cardiovascular disease, presence of diabetes mellitus, smoking history, and SPP < 70 mmHg as independent risk factors for lower limb survival and overall survival. Then, we constructed risk criteria using the significantly independent risk factors. We can clearly stratify lower limb survival and overall survival of the hemodialysis patients into 3 groups. Although the observation period is short, we conclude that SPP value has the potential to be a risk factor that predicts both lower limb survival and the prognosis of hemodialysis patients.

Post-transplant Renal Function and Cardiovascular Events Are Closely Associated With the Aortic Calcification Index in Renal Transplant Recipients

INTRODUCTION The aortic calcification index (ACI) is reported to be closely associated with renal dysfunction and cardiovascular events; however, its implication in renal transplant recipients has not been well examined. In this study, we investigated the relationship between pretransplant ACI, ACI progression, post-transplant renal function, and post-transplant cardiovascular events in renal transplant recipients. PATIENTS AND METHODS The study from June 1996 to Jan 2012 included 61 renal transplant recipients (living donors, 47; cadaveric donors, 14). The median follow-up period was 60 months. ACI was quantitatively measured on abdominal computed tomography. The relationship between age, dialysis period, estimated glomerular filtration rate (eGFR), and pre- and post-transplant ACI was longitudinally evaluated. Risk factors for post-transplant ACI progression were determined by logistic regression analysis. Patient background and the incidence of post-transplant cardiovascular events were also assessed. RESULTS The pretransplant ACI (median 4.2%) significantly correlated with age at transplant, dialysis period, and diabetes mellitus. ACI gradually increased up to 2.8 times at 10 years after transplantation. Post-transplant eGFR significantly correlated with ACI progression in patients with chronic kidney disease of stage ≥ 3. Logistic regression analyses showed that age at transplantation, post-transplant period, cadaveric donors, and post-transplant chronic kidney disease stage 3 were risk factors for post-transplant ACI progression. The pretransplant ACI was higher (median 66%) in 3 patients who experienced post-transplant cardiovascular events. CONCLUSIONS ACI progression closely correlates with age and post-transplant renal function. A high pretransplant ACI is a risk factor for post-transplant cardiovascular events in renal transplant recipients.

Efficacy of SMART Stent Placement for Salvage Angioplasty in Hemodialysis Patients with Recurrent Vascular Access Stenosis

Vascular access stenosis is a major complication in hemodialysis patients. We prospectively observed 50 patients in whom 50 nitinol shape-memory alloy-recoverable technology (SMART) stents were used as salvage therapy for recurrent peripheral venous stenosis. Twenty-five stents each were deployed in native arteriovenous fistula (AVF) and synthetic arteriovenous polyurethane graft (AVG) cases. Vascular access patency rates were calculated by Kaplan-Meier analysis. The primary patency rates in AVF versus AVG at 3, 6, and 12 months were 80.3% versus 75.6%, 64.9% versus 28.3%, and 32.3% versus 18.9%, respectively. The secondary patency rates in AVF versus AVG at 3, 6, and 12 months were 88.5% versus 75.5%, 82.6% versus 61.8%, and 74.4% versus 61.8%, respectively. Although there were no statistically significant difference in patency between AVF and AVG, AVG showed poor tendency in primary and secondary patency. The usefulness of SMART stents was limited in a short period of time in hemodialysis patients with recurrent vascular access stenosis.

Aberrant N-Glycosylation Profile of Serum Immunoglobulins is a Diagnostic Biomarker of Urothelial Carcinomas

The aim of this study to determine whether the aberrant N-glycosylated serum immunoglobulins (Igs) can be applied as a diagnostic marker of urothelial carcinoma (UC). Between 2009 and 2016, we randomly obtained serum available from 237 UC and also 96 prostate cancer as other cancer controls from our serum bank and also obtained—from 339 healthy volunteers (HV)—controls obtained from community-dwelling volunteers in Iwaki Health Promotion Project. A total of 32 types of N-glycan levels on Igs were determined by high-throughput N-glycomics and analyzed by multivariable discriminant analysis. We found five UC-associated aberrant N-glycans changes on Igs and also found that asialo-bisecting GlcNAc type N-glycan on Igs were significantly accumulated in UC patients. The diagnostic N-glycan Score (dNGScore) established by combination of five N-glycans on Igs discriminated UC patients from HV and prostate cancer (PC) patients with 92.8% sensitivity and 97.2% specificity. The area under the curve (AUC) for of the dNGScore was 0.969 for UC detection that was much superior to that of urine cytology (AUC, 0.707) and hematuria (AUC, 0.892). Furthermore, dNGScore can detect hematuria and urine cytology negative patients. The dNGscore based on aberrant N-glycosylation signatures of Igs were found to be promising diagnostic biomarkers of UCs.

Invadopodia are essential in transurothelial invasion during the muscle invasion of bladder cancer cells

Muscle invasive bladder cancer is an aggressive type of epithelial tumor with a high rate of metastasis. For bladder cancer cells to reach the muscle layer, cells must invade through an urothelial cell monolayer (transurothelial invasion) and basement membrane. However, the process by which transurothelial invasion occurs has not been fully characterized. In this study we developed a novel method to evaluate the transurothelial invasion capacity and investigated its cellular and molecular processes using primary culture cells from bladder cancer patients. The analysis revealed that compared with the prognosis for patients with non‑muscle invasive bladder cancer that of patients with muscle invasive bladder cancer was particularly poor due to metastatic recurrence. Cancer cells from patients with muscle invasive bladder cancer exhibited a higher invasive capacity through the urothelial cell monolayer compared with those from non‑invasive bladder cancer patients. Furthermore, muscle invasive bladder cancer cells demonstrated a greater ability to form invadopodia, the filamentous actin‑based membrane protrusions required for matrix degradation and invasion compared with non‑invasive cells. Bladder cancer cell lines were established with reduced invadopodia formation by silencing the expression of cortactin, an essential component of invadopodia. The cortactin knockdown bladder cancer cells with reduced invadopodia formation demonstrated a markedly reduced ability to invade through the urothelial cell monolayer, indicating that invadopodia are essential for transurothelial invasion. The results indicate that invadopodia formation is required for muscle invasion of aggressive bladder cancer cells.

Surgery without Blood Transfusion for Giant Paraganglioma in a Jehovah's Witness Patient

A retroperitoneal tumor was identified in a 57-year-old female belonging to Jehovahs Witnesses during a health check. Subsequent examination led to the suspicion of a right pheochromocytoma. The patient wished to be treated by bloodless surgery and consulted our hospital after being refused surgery by several hospitals. She signed a liability waiver for blood transfusion refusal. After obtaining consent for diluted autotransfusion and preoperative administration of erythropoietin, the surgery was scheduled. The tumor was attached to the inferior vena cava and left renal vein and engulfed the right renal artery and vein. The tumor and right kidney were removed en bloc. Operative time was 8 h and 18 min, with 1,770 ml of blood loss. The histopathological diagnosis was paraganglioma with the normal adrenal gland within the border of the tumor. The patient was discharged from the hospital with no postoperative complications.

Blood group antigen-targeting peptide suppresses anti-blood group antibody binding to antigen in renal glomerular capillaries after ABO-incompatible blood reperfusion.

Background Antibody-mediated rejection after ABO-incompatible kidney transplantation (ABO-I KTx) is a major barrier to transplantation success. The advent of immunosuppressive therapy has markedly improved graft survival in ABO-I KTx. However, compared with normal KTx, clinical conditions during ABO-I KTx are difficult to control because of overimmunosuppression. To reduce the need for immunosuppression, we aimed to develop a novel blood group antigen-neutralizing therapy. Methods We screened for an ABO blood group antigen-targeting peptide (BATP) by screening of T7 phage-displayed peptide library. After screening, hemagglutination inhibition assays, enzyme-linked immunosorbent assay, and cytotoxicity assay were used to analyze the blood group antigen-blocking effect and toxicity of BATP. We also tested the inhibitory effects on anti-blood group antibody binding in normal human kidney tissues blocked with BATP and excised kidneys perfused ex vivo with BATP. Results We identified six peptide sequences that efficiently suppressed hemagglutination of red blood cells by anti-ABO blood group antibodies and binding of these antibodies to ABO histo-blood group antigens in kidney tissues. Surprisingly, ex vivo perfusion of BATP in kidneys excised from renal cell carcinoma patients caused significant suppression of anti-blood group antibody binding to antigen and IgG and IgM deposition in renal glomerular capillaries after ABO-I blood reperfusion. Conclusions These data indicate that A/B blood group antigens on red blood cells and in kidney tissues may be neutralized by BATP. This approach may enable the development of a novel blood group antigen-neutralizing therapy to overcome the challenges of ABO-I KTx.

MP58-02 ABERRANT N-GLYCOSYLATION PROFILE OF SERUM IMMUNOGLOBULINS IS A DIAGNOSTIC BIOMARKER OF UROTHELIAL CARCINOMAS

RESULTS: In TCGA data, neither basal nor luminal markers levels significantly correlated with metastasis or lymphovascular invasion (LVI); P 1⁄4 0.2 to 0.9. Only KRT5 significantly but inversely correlated with lymph node (LN) positivity; P1⁄40.011. EGFR levels did not correlate with metastasis, LVI, or LN positivity; P > 0.05. In TCGA dataset 77 (18.9%), 50 (12.3%) and 14 (3.4%) expressed basal, luminal and DN subtypes, respectively; 266 (66.4%) patients did not conform to any group. In univariate or multivariate analyses, the subtypes also did not correlate with metastasis, LVI or LN status. Only luminal subtype associated with better OS; P1⁄40.003. However no subtype significantly correlated with RFS. In KM analysis no subtype stratified patients regarding RFS (P>0.2). Oncomine BCa datasets validated these results. CONCLUSIONS: TCGA and Oncomine datasets show that the majority of MIBCa tissues express a mixed pattern of basal and luminal markers. Furthermore, basal, luminal or DN subtypes do not associate with clinical parameters or prognosis of MIBCa patients.

Proton pump inhibitor as an independent factor of progression of abdominal aortic calcification in patients on maintenance hemodialysis

Backgrounds Proton pump inhibitors (PPIs) can be associated with vascular calcification in patients undergoing dialysis through hypomagnesemia. However, only few studies have demonstrated the influence of PPIs on vascular calcification in patients on maintenance hemodialysis (HD). This study aimed to investigate whether the use of PPIs accelerates vascular calcification in patients on HD. Materials and methods We retrospectively evaluated 200 HD patients who underwent regular blood tests and computed tomography (CT) between 2016 and 2017. The abdominal aortic calcification index (ACI) was measured using abdominal CT. The difference in the ACI values between 2016 and 2017 was evaluated as ΔACI. Patients were divided into PPI and non-PPI groups, and variables, such as patient background, medication, laboratory data, and ΔACI were compared. Factors independently associated with higher ΔACI progression (≥ third tertile value of ΔACI in this study) were determined using multivariate logistic regression analysis. Results The PPI and non-PPI groups had 112 (56%) and 88 (44%) patients, respectively. Median and third tertile value of ΔACIs were 4.2% and 5.8%, respectively. Serum magnesium was significantly lower in the PPI (2.1 mg/dL) than in the non-PPI (2.3 mg/dL) group (P <0.001). Median ΔACI was significantly higher in the PPI (5.0%) than in the non-PPI (3.8%) group (P = 0.009). A total of 77 (39%) patients had a higher ΔACI. Multivariate analysis revealed that PPIs (odds ratio = 2.23; 95% confidence interval = 1.11–4.49), annual mean calcium phosphorus product, ACI in 2016, baseline serum magnesium levels, and HD vintage were independent factors associated with higher ΔACI progression after adjusting for confounders. Conclusion PPI use may accelerate vascular calcification in patients on HD. Further studies are necessary to elucidate their influence on vascular calcification.