Photodynamic therapy exploiting the anti-tumor activity of mannose-conjugated chlorin e6 reduced M2-like tumor-associated macrophages.

M2-like tumor-associated macrophages (M2-TAMs) in cancer tissues are intimately involved in cancer immunosuppression in addition to growth, invasion, angiogenesis, and metastasis. Hence, considerable attention has been focused on cancer immunotherapies targeting M2-TAMs. However, systemic therapies inhibit TAMs as well as other macrophages important for normal immune responses throughout the body. To stimulate tumor immunity with fewer side effects, we targeted M2-TAMs using photodynamic therapy (PDT), which damages cells via a nontoxic photosensitizer with harmless laser irradiation. We synthesized a light-sensitive compound, mannose-conjugated chlorin e6 (M-chlorin e6), which targets mannose receptors highly expressed on M2-TAMs. M-chlorin e6 accumulated more in tumor tissue than normal skin tissue of syngeneic model mice and was more rapidly excreted than the second-generation photosensitizer talaporfin sodium. Furthermore, M-chlorin e6 PDT significantly reduced the volume and weight of tumor tissue. Flow cytometric analysis revealed that M-chlorin e6 PDT decreased the proportion of M2-TAMs and increased that of anti-tumor macrophages, M1-like TAMs. M-chlorin e6 PDT also directly damaged and killed cancer cells in vitro. Our data indicate that M-chlorin e6 is a promising new therapeutic agent for cancer PDT.

Changes in Peritoneal Transport and Peritoneal Damage in Japanese Patients Undergoing Peritoneal Dialysis Using Neutral-pH Dialysate: A Retrospective Cohort Study at Two Centers.

The effects of medium- or long-term use of neutral-pH dialysate on peritoneal transport and peritoneal damage have not been sufficiently researched.We retrospectively evaluated time-dependent changes in the dialysate-to-plasma ratio of creatinine (D/P Cr) and biomarkers of peritoneal damage in the effluent of 65 patients who underwent peritoneal dialysis (PD) with neutral-pH dialysate, including 48 who underwent medium-term PD (≥3 years) and 17 who underwent long-term PD (≥5 years).Patients who underwent medium-term PD initially had a D/P Cr of 0.59 (range: 0.53 - 0.74), nonsignificantly changing to 0.65 (range: 0.55 - 0.73), 0.67 (range: 0.56 - 0.74), and 0.67 (range: 0.62 - 0.72) after 1, 2, and 3 years respectively (p = 0.30, p = 0.26, and p = 0.19). Patients who underwent long-term PD initially had a D/P Cr of 0.57 (range: 0.52 - 0.62), nonsignificantly changing to 0.61 (range: 0.52 - 0.69), 0.64 (range: 0.54 - 0.67), 0.62 (range: 0.57 - 0.66), 0.65 (range: 0.50 - 0.72), and 0.61 (range: 0.48 - 0.7) after 1, 2, 3, 4, and 5 years respectively (p = 0.49, p = 0.31, p = 0.24, p = 0.23, and p = 0.46). After 3 years, a significant increase in effluent hyaluronan (HA) from 90 ng/mL initially (range: 66 - 121 ng/mL) to 144 ng/ mL (range: 116 - 216 ng/mL) was observed (p = 0.04).No significant change in D/P Cr was observed in patients who underwent PD with neutral-pH dialysate. However, effluent HA, which is a biomarker for peritoneal damage, increased. In patients using neutral-pH dialysate, D/P Cr cannot be a biomarker for determining PD discontinuation within 5 years, but effluent HA might be useful.

Using a Peritoneal Dialysis Access Simulator in Surgical Training for Nephrologists.

In Japan, peritoneal dialysis (PD) catheter insertion has been performed by both nephrologists and surgeons. However, nephrologists have fewer opportunities to train in the insertion procedure. We therefore used a PD access simulator to provide training in this operative technique for nephrologists. A PD access simulator developed by Terumo Medical Corporation was used for the training. The simulator uses a mannequin made of acrylic resin. The abdominal wall of a pig is attached to the abdominal area, and a plastic bag represents the abdominal cavity. The simulator enables the surgical procedure to be performed from skin incision to PD catheter insertion. Between October 2011 and December 2013, 3 supervising doctors used the simulator to guide 17 nephrologists with no experience through a PD catheter insertion. One-on-one training was provided in a single 2- or 3-hour session. In a questionnaire survey after the training, trainees gave high marks to the handling of surgical instruments, the environment of the operating room, and the surgical guidance during training. However, the supervising doctors required the ability to respond flexibly, because trainees had individual differences in skills. The PD access simulator might be useful for providing guided training in operative technique for PD catheter insertion.

A Comparison Study of Glucose Fluctuation During Automated Peritoneal Dialysis and Continuous Ambulatory Peritoneal Dialysis.

In recent years, it has become possible to examine an individual's daily glucose profile with a continuous glucose monitoring system (CGMS). The aim of the present study was to use a CGMS to evaluate the difference in glucose fluctuation between diabetic patients on automated peritoneal dialysis (APD) and those on continuous ambulatory peritoneal dialysis (CAPD). We retrospectively studied 20 diabetic patients on peritoneal dialysis (16 men, 4 women; mean age: 55 ± 10 years) who used a CGMS a total of 23 times (12 times by APD users, 11 times by CAPD users). The difference in the maximum and minimum blood glucose over 72 hours (ABG) and the standard deviation of blood glucose were used as indicators of glucose fluctuation. Average blood glucose levels as evaluated by CGMS and by glycosylated hemoglobin were not significantly different between the APD and CAPD patients. However, the ABG (181 ± 64 mg/dL vs. 238 ± 67 mg/dL, p = 0.02) and the standard deviation of blood glucose (36.3 ± 14.5 mg/dL vs. 49.2 ± 14.1 mg/dL, p = 0.03) were significantly lower in the APD patients than in the CAPD patients. The present study indicates that, compared with CAPD, APD might reduce glucose fluctuation in diabetic peritoneal dialysis patients.

Subcutaneous pathway diversion for peritoneal dialysis catheter salvage.

Peritoneal dialysis (PD) catheter-related infection is still is the most troublesome problem for continuation of PD without the need to switch to hemodialysis. We have been performing subcutaneous pathway diversion (SPD) as a surgical treatment for refractory exit-site and tunnel infection (ESTI). To clarify the efficacy and safety of SPD, we conducted a retrospective study. From August 2008 to August 2013, 30 SPDs were performed in 26 patients (16 men, 10 women; mean age: 58 +/- 13 years; 54% with diabetes; mean body mass index: 23.9 +/- 3.5 kg/ m2). The reasons for the SPDs were ESTI in 25 patients, and outer cuff extrusion in 1 patient. All patients resumed PD immediately after SPD, and the duration of hospitalization was 11.7 +/- 10.1 days. After SPD, one patient experienced a dialysate leak, and another patient experienced a mild subcutaneous hematoma. Another 4 patients developed exit-site infection (ESI) and underwent a second SPD. Of those 4 patients, 3 presented with another ESI unrelated to the first episode, and all developed an ESI after 6 months or more. The remaining 20 patients experienced no such complications. Furthermore, catheter survival after SPD was 17.4 +/- 13.4 months. To eradicate ESTTI we suggest that SPD, which does not require catheter removal or interruption of PD, is useful compared with the unroofing technique or catheter removal.

Efficacy of oral powder compared with chewable tablets for lanthanum carbonate administration in hemodialysis patients.

Lanthanum carbonate (LC) has been administered in a chewable tablet form for patients with hyperphosphatemia undergoing dialysis. However, some patients have difficulty chewing the tablets. LC oral powder has recently been released in Japan. The purpose of this study was to clarify the efficacy of LC oral powder form compared with that of chewable tablet form. The efficacy and safety of LC oral powder was retrospectively assessed in hemodialysis patients who switched from chewable tablet form to oral powder form without dose modification. Thirty-six patients (mean age, 66.8 ± 10.5 years; male, 64%; 39% with diabetes; mean duration of dialysis treatment, 99.2 ± 95.6 months) were enrolled in this study between June and July of 2012. Changes in clinical data and adverse events after the switch to oral powder form were investigated. The average dose of LC was 1180 ± 520 mg/day. Serum phosphorus levels were significantly decreased after the switch from chewable tablet form to oral powder form (5.3 ± 1.7 mg/dL at baseline vs. 4.9 ± 1.2 mg/dL at after 1 month after, P = 0.038). In contrast, no significant differences were observed in serum calcium and parathyroid hormone levels. Furthermore, no significant differences were evident in weight gain after the switch to oral powder form (2.5 ± 1.2 kg at baseline vs. 2.4 ± 1.1 kg at 1 month after the switch, P = 0.29). No serious adverse events were recorded. Our results suggest that LC is more effective in oral powder form than chewable tablet form for hemodialysis patients.

The first case report of peritoneal dialysis related peritonitis caused by Microbacterium paraoxydans.

Peritonitis is still the major complication associated with peritoneal dialysis (PD). Microbacterium spp., a type of coryneform bacteria, is an environmental bacterium isolated from soil, waste water and animals. Human infection is rare, and only few cases have so far been reported in immunocompromised hosts, such as PD patients. Microbacterium paraoxydans, one type of Microbacterium spp. was identified for the first time in 2003. Only two cases of infection of Microbacterium paraoxydans have so far been reported. We herein report the first case of PD-related peritonitis caused by Microbacterium paraoxydans, which was identified by a sequence determination of the 16S rRNA gene. Based on the results of antibiotic sensitivity, the intravenous administration of erythromycin (EM) and oral administration of sulfamethoxazole/trimethoprim (ST) were selected, and PD was interrupted. EM administration was stopped after a total of 14 days. ST was administered for a total of 21 days, and later PD was resumed. Thereafter, no recurrence or relapse of peritonitis without removal of the PD catheter was observed. Microbacterium spp. exhibits multidrug resistance and such an infection is refractory in many cases. We assume that both accurate species identification and the use of antibiotic sensitivity tests are essential to effectively treat this kind of infection.

Physical activity is associated with serum albumin in peritoneal dialysis patients.

The incidence of metabolic syndrome is about 50% in peritoneal dialysis (PD) patients. The positive association of metabolic syndrome with lower physical activity (PA) has been reported in the general population, but the effect of PA in PD patients has not been clarified. The purpose of the present study was to evaluate PA in PD patients and to clarify the correlations between PA and various clinical parameters in PD patients. We assessed 38 PD patients (22 men; age: 63.9 +/- 10.8 years; body mass index: 24.0 +/- 3.9; 15 with diabetes) who had been treated with PD at least for 3 months. We defined PA as the average number of steps per day measured using a pedometer for 1 month. Blood biochemical findings and dialysis adequacy were measured as clinical parameters. Of the 38 patients, only 11 (29%) reached the steps per day of healthy individuals. In addition, steps per day were significantly correlated with serum albumin (r = 0.45, p = 0.01), C-reactive protein (r = -0.33, p = 0.04), and age (r = -0.34, p = 0.04). Multiple regression analysis showed that serum albumin was the only variable that significantly correlated with steps per day (beta = 0.42, p = 0.01). Our study showed that PA declines significantly in PD patients, which might correlate with malnutrition-inflammation-atherosclerosis syndrome.

Prothrombin fragment 1 + 2 (F1 + 2) in effluent is a useful marker for peritoneal permeability in peritoneal dialysis patients using neutral dialysate.

To clarify the influence of neutral dialysate (ND) on peritoneum, we examined changes in peritoneal permeability and in various markers of the coagulation and fibrinolytic system in effluent and the correlations between peritoneal permeability and those markers in peritoneal dialysis (PD) patients using ND. We evaluated 14 patients (8 men, 6 women; mean age: 58.6 +/- 12.0 years) who started PD using ND. The peritoneal equilibration test (PET) was performed to assess dialysate-to-plasma ratio for creatinine (D/P Cr) as peritoneal permeability. Coagulation markers [thrombin-antithrombin complex, fibrin monomer (FM), prothrombin fragment 1+2 (F1 + 2)] and fibrinolytic markers (fibrin degradation products, D-dimer) in effluent were also measured. At 2 years, FM in effluent was significantly lower (p = 0.006). The other markers and the D/P Cr did not change significantly. At the initiation of PD and at 2 years, D/P Cr was significantly correlated with F1 + 2 (r = 0.70 and 0.76 respectively, p < 0.01). Furthermore, multiple regression analysis showed that only F1 + 2 was correlated with D/P Cr at 2 years (r = 0.79, p = 0.004). These results suggest that ND has little influence on coagulation and fibrinolytic markers in effluent. In addition, F1 + 2 is a useful marker for peritoneal permeability in PD patients using ND.