Pharmacokinetics, efficacy and safety of daclatasvir plus asunaprevir in dialysis patients with chronic hepatitis C: pilot study.

The aim of this study was to evaluate the pharmacokinetic profile of daclatasvir (DCV) and asunaprevir (ASV) dual therapy in haemodialysis patients infected with hepatitis C virus (HCV). Eighteen haemodialysis patients and 54 patients with normal renal function were treated with DCV and ASV dual therapy for 24 weeks. We evaluated the pharmacokinetic profiles of DCV and ASV and examined the rate of sustained virological response 12 weeks after the end of treatment (SVR12 ) and incidence of adverse events during treatment of haemodialysis patients infected with chronic HCV genotype 1 infection. To adjust for potential differences in baseline characteristics between haemodialysis patients and patients with normal renal function, we used propensity scores case-control matching methods. Area under the plasma concentration time curve from 0 to 6 h (AUC0-6 h ) of DCV was slightly lower in haemodialysis patients than in patients with normal renal function (P > 0.6). AUC0-6 h of ASV was significantly lower in haemodialysis patients (P = 0.012). SVR12 rates were 100% (18/18) for haemodialysis and 96.2% (52/54) for patients with normal renal function. Changes in mean log10 HCV RNA levels and viral response were higher in haemodialysis patients compared to patients with normal renal function. No discontinuations due to adverse events occurred. In conclusion, DCV and ASV dual therapy for HCV infection is effective and safe with similar results in haemodialysis patients compared to patients with normal renal function.

Isolated Pulmonary Cryptococcosis Confused with Lung Tumor 5 Years After Kidney Transplantation: A Case Report.

BACKGROUND: In transplant recipients, due to the use of immunosuppressive therapy, it is occasionally difficult to distinguish between an infection and malignancy, especially in the case of a lung lesion. Here, we report a case of isolated pulmonary cryptococcosis after kidney transplantation that was difficult to distinguish from a lung tumor. CASE REPORT: A 52-year-old man underwent a kidney transplant from his mother when he was 44 years old. Immunosuppression was maintained with tacrolimus, methylprednisolone, and mycophenolate mofetil. His post-transplant course was uneventful and serum creatinine levels were maintained. Five years post-transplantation, a non-contrast computed tomography (CT) examination revealed a nodule measuring 3 mm in diameter in the middle lobe of the right lung. The nodule gradually increased to 12 mm in 2 years. Positron emission tomography/CT examination showed a maximum standardized uptake value of 0.5 for the nodule. Biochemical examination revealed no elevation in total leucocyte count and C-reactive protein levels. However, tumor markers were elevated: serum carcinoembryonic antigen, 5.9 ng/mL; pro-gastrin-releasing peptide, 84.6 pg/mL. Furthermore, the serum cryptococcus antigen was negative. Therefore, thoracoscopic partial lung resection was performed. Pathologically, a number of spherical fungi from the necrotic substance of the tumor were confirmed positive by periodic acid-Schiff and Grocott-Gomori staining. The patient was therefore diagnosed with pulmonary cryptococcosis. Two years later, the patient is alive and has shown no evidence of recurrence. CONCLUSIONS: In lung nodules after kidney transplantation, even if serum cryptococcus antigen is not identified, it is necessary to keep in mind the possibility of pulmonary cryptococcosis.

15-Ketoprostaglandin delta 13-reductase activity in bovine ocular tissues.

The present study provides the first evidence for delta 13-reduction of 15-ketoprostaglandins (15-keto-PGs) by bovine ocular tissues. The 9,000xg supernatants of cornea, iris, ciliary body, retina, and RPE-choroid except lens exhibited delta 13-reductase activity toward 15-keto-PG E2 and F2 alpha in the presence of NADPH or NADH as an electron donor. Among the tissues tested, the highest activity was observed in ciliary body and iris, followed by RPE-choroid, retina, and cornea. The NADPH- and NADH-linked double bond reductase activities were inhibited by dicumarol, quercitrin, indomethacin and disulfiram, but not by potassium cyanide. NADPH-linked 15-keto-PG F2 alpha delta 13-reductase was purified from bovine iris-ciliary body cytosol by fractionation with ammonium sulfate and high performance liquid chromatography (HPLC) with TSK gel DEAE-5PW, and TSK gel Blue-5PW. The purified enzyme was homogenous by the criterion of sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Its molecular weight was estimated to be about 57,000 by electrophoresis, and about 55,000 by gel filtration HPLC with Superose 12.

Oxidation of 1,1-diphenylhydrazine to N-nitrosodiphenylamine by superoxide radical in the eye.

By microsomes obtained from bovine ciliary body, 1,1-diphenylhydrazine was oxidized to N-nitrosodiphenylamine in the presence of NADPH. This reaction was stimulated by riboflavin which was recognized to be an electron carrier. The oxidizing activity by microsomes was markedly inhibited by superoxide dismutase, but not by SKF 525-A or carbon monoxide. Similarly, the oxidation of 1,1-diphenylhydrazine to its corresponding nitrosamine occurred in varying degrees when the hydrazine derivative was exposed to visible light in the presence of photosensitizers such as riboflavin, flavin adenine dinucleotide, flavin mononucleotide, lumiflavin, lumichrome, NAD+, NADH, NADP+, or NADPH. The photochemical oxidation was inhibited by active oxygen-scavengers such as superoxide dismutase, L-ascorbic acid or alpha-tocopherol. The superoxide radical involved in the photochemical reaction was determined by measuring the oxidation of epinephrine to adrenochrome. The oxidation of epinephrine was well correlated to that of 1,1-diphenylhydrazine. Thus, the present study provided evidence that the superoxide radical is responsible for the oxidation of a hydrazine derivative to a corresponding nitrosamine by ocular tissue microsomes and by photosensitizers.

Hemodialysis together with peritoneal dialysis is one of the simplest ways to maintain adequacy in continuous ambulatory peritoneal dialysis.

When long-term peritoneal dialysis (PD) is performed without change in the dialysis prescription, uremic symptoms appear owing to insufficient dialysis dose. In such cases, an increase in dialysate volume is required, but this increase is difficult to obtain in all patients owing to limitations in abdominal volume, lifestyle, or body weight. A combination of PD and hemodialysis (HD) is the simplest method of overcoming these limitations. Combination therapy--HD once per week for 4 hours and PD 6 days per week--was performed in our patients. The total weekly dialysis dose (urea) was calculated as follows: to convert the dialysis dose by HD to that of continuous treatment, the equivalent renal urea clearance (EKR) was calculated and added to the dialysis dose by PD. Combination therapy was performed in 12 patients. The reasons for the combination therapy included ultrafiltration (UF) loss in 2 patients, uremic symptoms in 3 patients, poor fluid management in 5 patients, umbilical hernia in 1 patient, and hydrothorax in 1 patient. Total Kt/V per week was increased from 1.61 +/- 0.19 to 2.05 +/- 0.25 in these patients. In the 2 patients with UF loss, weight control became easier after the combination therapy was started, and this control was possible with hypotonic dialysate alone. In patients with uremic symptoms, the symptoms improved; furthermore, dermal pigmentation improved in these patients. In summary, the dialysis dose was increased and body fluids became controllable after inducing combination therapy, resulting in improvement uremic symptoms and increased quality of life.

Necessity of correcting cancer antigen 125 appearance rates by body surface area.

Attention has been focused on cancer antigen 125 (CA125) levels in dialysate as an index for evaluating the severity of peritoneal mesothelial cell impairment. However, the method of evaluating CA125 levels in the dialysate has not been standardized. We determined that CA125 levels in the dialysate should be corrected by body surface area (BSA). Using 51 patients who had been undergoing peritoneal dialysis (PD), CA125 levels in the dialysate were measured to evaluate the appearance rate of CA125 (CA125AR). Because only 18 of the 51 patients (35%) had a BSA greater than 1.73 m2, CA125 levels in the dialysate might be underestimated in other patients when absolute values of CA125 are not corrected by BSA. When correlations between corrected CA125AR and various parameters were evaluated, corrected CA125AR positively correlated with age, but negatively correlated with serum creatinine and albumin levels. Moreover, no positive correlation was seen between corrected CA125AR and the duration of PD or the peritoneal permeability test. However, in 5 patients with ultrafiltration loss after prolonged PD, the values of CA125AR persistently or rapidly decreased before transfer to hemodialysis. Although CA125 can be used as an index of peritoneal deterioration, the absolute value of CA125 should be corrected by BSA. However, it is most important to evaluate changes in CA125 in individual patients.

Surgical treatment for sclerosing encapsulating peritonitis.

Sclerosing encapsulating peritonitis (SEP) is recognized as a serious complication of continuous ambulatory peritoneal dialysis (CAPD). To date, in our hospital, 12 cases of SEP have been successfully treated by active intervention. The development of SEP was observed in these patients after removal of a peritoneal catheter. SEP was relieved by steroid administration in 3 of these patients, and by total parenteral nutrition (TPN) performed after exploratory laparotomy in 1 patient. In the remaining 8 patients, SEP was relieved by total intestinal enterolysis. In patients who underwent total intestinal enterolysis, the severity of encapsulation and adhesion varied. White, rigid encapsulation was observed in 4 patients who had been treated by peritoneal dialysis (PD) for less than 10 years. Seemingly normal serosae were observed under the capsules, and total intestinal enterolysis was easily performed in these patients. In the patient who underwent renal transplantation, more severe intestinal adhesion was observed, although the duration of PD was limited to 70 months and the intestinal serosae were seemingly normal. These findings were considered specific to SEP developing after immunosuppressant administration. In 3 patients who had undergone PD for more than 10 years, degeneration of the visceral peritoneum was observed, together with an ill-defined boundary between the capsules and the serosae. Therefore, total enterolysis was performed in these patients, including a wide area of the muscular layer. Furthermore, calcification was observed in several regions, where the capsules were severely adherent to the parietal peritoneum. The post-operative course for all 8 patients was satisfactory, and these patients finally returned to their previous social activities. We conclude that when SEP symptoms are not improved by steroid administration or TPN, active total intestinal enterolysis should be performed. However, it is absolutely important to avoid inducing anastomosis or impairing the intestine.

Treatment options for encapsulating peritoneal sclerosis based on progressive stage.

Sclerosing encapsulating peritonitis (SEP) is recognized as a serious complication of peritoneal dialysis. However, recovery is possible if an appropriate diagnosis and treatment are made. The term SEP is used most often, but is inaccurate, particularly the reference to peritonitis. A more accurate description would be "encapsulating peritoneal sclerosis" (EPS). From the therapeutic perspective, the diagnosis should be established before EPS develops. Early diagnosis is important. Furthermore, it is also important to determine the therapeutic tactics for EPS according to the disease stage. Most cases of EPS develop with manifestations of fever, increased levels of C-reactive protein (CRP), and slight ileus symptoms, accompanied by increased ascites ("inflammatory stage"). Following precise identification of the inflammatory stage, steroid administration should be initiated immediately with the onset of EPS. Methylprednisolone pulse therapy is recommended during the early stage. If the EPS is not relieved, or if it recurs within 1 month, the steroid dose should be decreased and the patient should be managed by total parenteral nutrition (TPN) ("encapsulating stage"). If ileus symptoms remain despite the absence of inflammatory findings and decreased ascites, laparotomy and enterolysis should be considered within 6 months ("ileus stage"). However, it is important that the enterolysis be performed without damaging the capsule-covered intestine. To date, we have successfully treated EPS in 18 of 19 patients using these options. In 3 patients, EPS was relieved by steroid administration. In 15 patients, EPS was relieved by total intestinal enterolysis. Enterolysis patients had satisfactory operative outcomes and eventually returned to their previous social activities. One patient experienced perforation of the small intestine and pan-peritonitis, and died of sepsis. In summary, EPS is not an incurable disease. It can be completely overcome by active diagnosis and treatment.

Development and clinical application of a new CAPD connection system--Safedap.

To perform continuous ambulatory peritoneal dialysis (CAPD), a safe and easy bag exchange system must be established. The authors developed a new system called "Safedap" and applied it to clinical cases. Safedap consists of a bottom, a sleeve, a shell, and a lock-type connector. The bottom and sleeve are made into one unit with a preembedded sponge saturated with 10% povidone-iodine for disinfection and protection. Safedap was introduced to 23 patients who were observed for a period of 293 patient months. Sixteen patients used a standard spike and functioned as controls. Peritonitis rates were 1/73.3 patient months in Safedap (4 episodes in 3 patients) and 1/30.1 patient months in controls (10 episodes in 7 patients; p less than 0.05). Using life table analysis, the probability of a control being peritonitis free at 12 months was 0.63 versus 0.95 in those using Safedap (p less than 0.05). By allowing completion of bag exchanges safely and rapidly, Safedap is effective in reducing the occurrence rate of peritonitis.

Relationship between erythropoietin and chronic heart failure in patients on chronic hemodialysis.

In the present study, the relationship between the blood erythropoietin level and cardiac function was investigated in 15 patients on chronic hemodialysis who developed chronic heart failure. Another 45 patients without cardiac dysfunction were selected as a control group that was matched for gender, age, and the duration of dialysis. The erythropoietin level was 256.3 +/- 481.8 mU/ml in the heart failure group, which was significantly higher than that in the control group (17.0 +/- 10.0 mU/ml, P < 0.01). Eight of the 15 patients in the heart failure group maintained a hematocrit of more than 30% without receiving recombinant human erythropoietin therapy, whereas 29 of the 45 patients in the control group required erythropoietin. In the heart failure group, the erythropoietin level was significantly correlated with the levels of atrial natriuretic peptide and brain natriuretic peptide (P < 0.01). These results suggest that heart failure can increase the erythropoietin level in proportion to the severity of cardiac dysfunction, even in patients on long-term dialysis.