Prevalence and characteristics of hepatitis E virus infection in kidney transplant recipients: A single-center experience in Japan.

BACKGROUND: Hepatitis E virus (HEV) infection can lead to chronic hepatitis in solid organ transplant recipients. To investigate whether HEV infection influences outcomes following kidney transplantation, we examined the prevalence of HEV infection and clinical characteristics of kidney transplant recipients in our hospital. METHODS: Our cross-sectional study included 184 kidney transplant recipients. Blood samples were obtained from all patients to detect anti-HEV immunoglobulin (Ig)A, IgM, and IgG by enzyme-linked immunosorbent assay and HEV RNA by reverse transcription polymerase chain reaction. Clinical data were collected from medical charts for all patients. RESULTS: The prevalence of anti-HEV IgG was 8/184 (4.3%). Anti-HEV IgA, anti-HEV IgM, and HEV RNA were not detected in any patients. Compared to their anti-HEV IgG-negative counterparts, anti-HEV IgG-positive patients were significantly older at the time of transplantation, and they were more likely to receive kidneys from deceased donors. No significant differences in other characteristics such as the prevalence of primary cause of end-stage renal disease, blood transfusion, and immunosuppressive therapy use; liver and renal function; and the frequencies of hepatitis B and hepatitis C virus infection were observed according to the patients' anti-HEV IgG status. CONCLUSION: HEV infection had no significant influence on the outcomes of kidney transplantation at our institution. However, HEV infection should be recognized in kidney transplant recipients similarly as hepatitis B and hepatitis C virus infection in cases of liver dysfunction.

Conversion From Steroid to Everolimus in Maintenance Kidney Transplant Recipients With Posttransplant Diabetes Mellitus.

OBJECTIVES: Although steroid withdrawal has been attempted to ameliorate various complications in kidney transplant recipients, a steroid-sparing strategy has more frequently led to acute rejection. We investigated the use of everolimus to safely overcome steroid withdrawal in kidney transplant recipients with posttransplant diabetes mellitus under maintenance immunosuppressive therapy. MATERIALS AND METHODS: A total of 75 de novo consecutive kidney transplant recipients received conventional immunosuppressive therapy comprising tacrolimus (trough level of 5 ng/mL), mycophenolate mofetil (1000 mg), and methylprednisolone (4 mg). Patients with posttransplant diabetes mellitus underwent simultaneous everolimus administration (trough level of 3-5 ng/mL) and steroid withdrawal at 1 to 15 months after transplant. Graft outcomes were compared between the everolimus and steroid groups. In the everolimus group, renal function and hemoglobin A1c levels at 12 months after administration were compared with values before everolimus administration. RESULTS: The mean posttransplant follow-up period in the everolimus (n = 25) and steroid (n = 50) groups was 672 and 747 days, respectively. All grafts survived in both groups, and biopsy-proven acute rejection rates did not significantly differ between the groups (16% vs 12%; P = .72). Furthermore, no acute rejection occurred after everolimus administration. In the everolimus group, hemoglobin A1c significantly declined at 9 months after everolimus administration (6.94% vs 6.53%; P = .047). In addition, both serum creatinine levels and estimated glomerular filtration rates in the everolimus group were stable for 12 months after everolimus administration. CONCLUSIONS: Steroid withdrawal using everolimus as maintenance immunosuppressive therapy for kidney transplant recipients may safely ameliorate posttransplant diabetes mellitus, achieve better glycemic control, and maintain stable renal function.

Renal Transplantation with Simultaneous Aortoiliac Reconstruction Using a Polytetrafluoroethylene Vascular Graft for Severe Atherosclerosis.

Studies on aortoiliac reconstruction for severe atherosclerosis with renal transplantation are limited. Here, we report a rare experience of the simultaneous reconstruction of the external iliac artery caused by severe atherosclerosis with polytetrafluoroethylene vascular graft and renal transplantation in a 55-year-old female; she was unable to undergo standard renal artery anastomosis to the right external iliac artery because of severe atherosclerosis, which would result in complete occlusion. Next, we directly anastomosed the donor renal artery to the polytetrafluoroethylene graft. After transplantation, delayed graft function occurred; therefore, the patient had to undergo hemodialysis. On day 7 after transplantation, her creatine level started to decrease. She was discharged from the hospital on the 14th day after transplantation. After 1 month, her serum creatinine level reduced to 1.12 mg/dL. After 3 years of transplantation, her serum creatinine level was 1.2 mg/dL. The simultaneous implantation of the polytetrafluoroethylene graft and renal transplantation was feasible as well as safe, with no infectious complications and stable renal function noted on long time follow-up. Although our case was rare, it emphasizes the need for transplant surgeons to gain surgical skills for vascular surgery using vascular grafts.

Biological and Clinical Effects of Calciprotein Particles on Chronic Kidney Disease-Mineral and Bone Disorder.

Calciprotein particles (CPPs) are a new biological marker of chronic kidney disease-mineral and bone disorder (CKD-MBD). CPPs consist of phosphate, calcium, and some proteins, with phosphate being the major contributor to the level and biological activity of CPPs. Recent studies have shown the physiological and pathological significance of CPPs, including contributions to bone and mineral metabolism, and to tissue and organ impairments such as cardiovascular damage and inflammatory responses. These actions are well known as important aspects of CKD-MBD. Fibroblast growth factor 23 (FGF23), which is secreted from the bone as the phosphaturic hormone, is markedly elevated in CKD-MBD. Many clinical studies have shown significant relationships between the level of FGF23 and outcomes such as mortality, prevalence of cardiovascular disease, bone fracture, and levels of inflammatory markers. Basic and clinical studies have suggested that CPPs contribute to synthesis and secretion of FGF23. Surgical treatments such as renal transplantation and parathyroidectomy for patients with CKD-MBD suppress excess levels of phosphate, calcium, parathyroid hormone (PTH), and FGF23, which are related to the CPP level. Therefore, suppression of CPPs might also contribute to improved clinical outcomes after these treatments.

The impact of preserved Klotho gene expression on antioxidative stress activity in healthy kidney.

Klotho, which was originally identified as an antiaging gene, forms a complex with fibroblast growth factor 23 receptor in the kidney, with subsequent signaling that regulates mineral metabolism. Other biological activities of Klotho, including antiaging effects such as protection from various types of cellular stress, have been shown; however, the precise mechanism of these effects of Klotho gene in the healthy human kidney is not well understood. In this study, we examined the relationships of Klotho and antioxidative stress gene expression levels in zero-hour biopsy specimens from 44 donors in kidney transplantation and verified them in animal models whose Klotho gene expression levels were varied. The nitrotyrosine expression level in the kidney was evaluated in these animal models. Expression levels of Klotho gene were positively correlated with the p53 gene and antioxidant enzyme genes such as catalase, superoxide dismutase 1 (SOD1), SOD2, peroxiredoxin 3 (PRDX3), and glutathione peroxidase 1 (GPX1) but not clinical parameters such as age and renal function or pathological features such as glomerulosclerosis and interstitial fibrosis tubular atrophy. The expression levels of all genes were significantly higher in mice with Klotho overexpression than in wild-type mice, and those except for catalase, PRDX3, and GPX1 were significantly lower in Klotho-deficient mice than in wild-type littermate mice. Nitrotyrosine-positive bands of various sizes were observed in kidney from Klotho-deficient mice only. The preservation of Klotho gene expression might induce the antioxidative stress mechanism for homeostasis of healthy human kidney independently of its general condition, including age, renal function, and histological findings.

Acquired von Willebrand Syndrome Complicating Nephrotic Syndrome: A Case of a Patient With Membranous Nephropathy.

Acquired von Willebrand syndrome (AVWS) is a rare clinical entity presenting with heterogeneous hemorrhagic manifestations, although some subsets of patients with AVWS may be asymptomatic until they are exposed to major trauma, an invasive procedure, or surgery. We herein report one such case in a 73-year-old male patient with nephrotic syndrome with a prolonged active partial thromboplastin time. We initially did not deal with this distinct abnormal clotting profile seriously, but persistent bleeding after a retroperitoneoscopic-assisted renal biopsy that allowed us to ascribe his nephrotic syndrome to membranous nephropathy fortuitously led to the discovery of concurrent AVWS. We feel that an accurate and prompt diagnosis as well as awareness of the disease remain a challenge for physicians and therefore strongly recommend the further accumulation of experiences similar to our own in a prospective manner. This report underscores the pitfalls associated with determining the bleeding risk, including an insufficient assessment and improper weighting of an abnormal clotting profile prior to the invasive procedure. Several management concerns that emerged in the current case are also discussed.

No significant differences in short-term renal prognosis between living kidney donors with and without diabetes.

BACKGROUND: Renal prognosis in living kidney donors with diabetes is currently not known. In this study, we sought to investigate renal prognosis in living kidney donors with diabetes. METHODS: We retrospectively investigated 241 living kidney donors who underwent nephrectomy at Jichi Medical University Hospital between January 2000 and December 2015. Donors with a follow-up period of less than 1 year were excluded. The remaining donors were divided into a diabetic group and a non-diabetic group. Their clinical parameters before donation and renal prognosis after donation were compared. RESULTS: Of the 241 donors, 16 were excluded due to their follow-up period being less than 1 year. Of the remaining 225 donors, 14 were diabetic and 211 were non-diabetic. There were no significant differences in variables at pre-donation. The median follow-up period was 4.3 (1.5-10.7) and 4.6 (1.0-13.0) years in kidney donors with and without diabetes, respectively. At the end of follow-up, the estimated glomerular filtration rate was 51.7 ± 7.1 ml/min/1.73 m2 in the diabetic group and 52.1 ± 12.2 ml/min/1.73 m2 (p = 0.906) in the non-diabetic group; urine albumin excretion was 9.5 (2-251) mg/day (or mg/g creatinine) in the diabetic group and 6 (0-626) mg/day (or mg/g creatinine) in the non-diabetic group (p = 0.130); and urine protein excretion was 0.079 (0-0.41) g/day in the diabetic group and 0.051 (0-3.7) g/day in the non-diabetic group (p = 0.455). CONCLUSIONS: There were no significant differences in short-term renal prognosis between kidney donors with and without diabetes.

Peritoneal Dialysis and Retroperitoneal Laparoscopic Radical Nephrectomy: A Favorable Experience With a Patient Complicated by Renal Cell Carcinoma.

Peritoneal dialysis (PD) is an accepted modality for managing end-stage kidney disease. We herein report a 75-year-old female patient on chronic PD who was complicated by renal cell carcinoma. She was successfully treated with retroperitoneal laparoscopic radical nephrectomy followed by a prompt resumption of the procedure. Various surgeries disturbing the abdominal wall integrity often disrupt the regular PD schedule, and using minimally invasive approaches is therefore an attractive therapeutic option. Our experience emphasizes the feasibility and safety of a retroperitoneal approach-based laparoscopic technique based on several empirical examples. However, systemic studies on this topic are obviously lacking, so we strongly recommend the accumulation of more cases similar to our own. Several surgical concerns that need to be dealt with among PD patients are also discussed.

Markov chain Monte Carlo analysis for the selection of a cell-killing model under high-dose-rate irradiation.

PURPOSE: High-dose-rate irradiation with 6 MV linac x rays is a wide-spread means to treat cancer tissue in radiotherapy. The treatment planning relies on a mathematical description of surviving fraction (SF), such as the linear-quadratic model (LQM) formula. However, even in the case of high-dose-rate treatment, the repair kinetics of DNA damage during dose-delivery time plays a function in predicting the dose-SF relation. This may call the SF model selection into question when considering the dose-delivery time or dose-rate effects (DREs) in radiotherapy and in vitro cell experiments. In this study, we demonstrate the importance of dose-delivery time at high-dose-rate irradiations used in radiotherapy by means of Bayesian estimation. METHODS: To evaluate the model selection for SF, three types of models, the LQM and two microdosimetric-kinetic models with and without DREs (MKMDR and MKM) were applied to describe in vitroSF data (our work and references). The parameters in each model were evaluated by a Markov chain Monte Carlo (MCMC) simulation. RESULTS: The MCMC analysis shows that the cell survival curve by the MKMDR fits the experimental data the best in terms of the deviance information criterion (DIC). In the fractionated regimen with 30 fractions to a total dose of 60 Gy, the final cell survival estimated by the MKMDR was higher than that by the LQM. This suggests that additional fractions are required for attaining the total dose equivalent to yield the same effect as the conventional regimen using the LQM in fractionated radiotherapy. CONCLUSIONS: Damage repair during dose-delivery time plays a key role in precisely estimating cell survival even at a high dose rate in radiotherapy. Consequently, it was suggested that the cell-killing model without repair factor during a short dose-delivery time may overestimate actual cell killing in fractionated radiotherapy.

Febuxostat for the Prevention of Recurrent 2,8-dihydroxyadenine Nephropathy due to Adenine Phosphoribosyltransferase Deficiency Following Kidney Transplantation.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder that results in irreversible renal damage due to 2,8-dihydroxyadenine (DHA) nephropathy. A 28-year-old man underwent living-related kidney transplantation for chronic kidney disease of unknown etiology. Numerous spherical brownish crystals observed in his urinary sediment on postoperative day 3 and were observed within the tubular lumen of renal allograft biopsy specimens on postoperative day 7. After a genetic diagnosis, febuxostat treatment was started on postoperative day 7, with the dosage gradually increased to 80 mg/day until complete the disappearance of 2,8-DHA crystals. Febuxostat prevented secondary 2,8-DHA nephropathy after kidney transplantation.

Educational Activity for the Radiation Emergency System in the Northern Part of Japan: Meeting Report on "The 3rd Educational Symposium on Radiation and Health (ESRAH) by Young Scientists in 2016".

In the northern part of Japan, close cooperation is essential in preparing for any possible emergency response to radiation accidents because several facilities, such as the Low-Level Radioactive Waste Disposal Facility, the MOX Fuel Fabrication Plant and the Vitrified Waste Storage Center, exist in Rokkasho Village (Aomori Prefecture). After the accident at Fukushima Daiichi Nuclear Power Plant in 2011, special attention should be given to the relationship between radiation and human health, as well as establishing a system for managing with a radiation emergency. In the area of Hokkaido and Aomori prefectures in Japan, since 2008 an exchange meeting between Hokkaido University and Hirosaki University has been held every year to have opportunities to discuss radiation effects on human health and to collect the latest news on monitoring environmental radiation. This meeting was elevated to an international meeting in 2014 titled "Educational Symposium on Radiation and Health (ESRAH) by Young Scientists". The 3rd ESRAH meeting took place in 2016, with the theme "Investigating Radiation Impact on the Environmental and Health". Here we report the meeting findings on the continuing educational efforts after the Fukushima incident, what was accomplished in terms of building a community educational approaches, and future goals.

Screening for hereditary angioedema (HAE) at 13 emergency centers in Osaka, Japan: A prospective observational study.

Hereditary angioedema (HAE) with deficiency of C1 inhibitor (C1-INH) is an autosomal-dominant disease characterized by recurrent episodes of potentially life-threatening angioedema. The objective is to study the incidence of HAE among patients who visit the emergency department.This was a 3-year prospective observational screening study involving 13 urban tertiary emergency centers in Osaka prefecture, Japan. Patients were included if they met the following criteria: unexplained edema of the body, upper airway obstruction accompanied by edema, anaphylaxis, acute abdomen with intestinal edema (including ileus and acute pancreatitis), or asthma attack. C1-INH activity and C4 level were measured at the time of emergency department admission during the period between July 2011 and June 2014.This study comprised 66 patients with a median age of 54.0 (IQR: 37.5-68.3) years. Three patients were newly diagnosed as having HAE, and 1 patient had already been diagnosed as having HAE. C1-INH activity levels of the patients with HAE were below the detection limit (<25%), whereas those of non-HAE patients (n = 62) were 106% (IQR: 85.5%-127.0%) (normal range, 70%-130%). The median level of C4 was significantly lower in the patients with HAE compared with those without HAE (1.2 [IQR: 1-3] mg/dL vs 22 [IQR: 16.5-29.5] mg/dL, P < 0.01) (normal range, 17-45 mg/dL).Three patients with undiagnosed HAE were diagnosed as having HAE in the emergency department during the 3-year period. If patients have signs and symptoms suspicious of HAE, the levels of C1-INH activity and C4 should be measured.

Modeling cell survival and change in amount of DNA during protracted irradiation.

Hyper-radiosensitivity (HRS) is a well-known bioresponse under low-dose or low-dose-rate exposures. Although disorder of the DNA repair function, non-targeted effects and accumulation of cells in G2 have been experimentally observed, the mechanism for inducing HRS by long-term irradiation is still unclear. On the basis of biological experiments and a theoretical study, we have shown that change in the amount of DNA associated with accumulation of cells in G2 enhances radiosensitivity. To demonstrate continuous irradiation with 250 kVp X-rays, we adopted a fractionated regimen of 0.186 or 1.00 Gy per fraction at intervals of 1 h (i.e. 0.186 Gy/h, 1.00 Gy/h on average) to Chinese Hamster Ovary (CHO)-K1 cells. The change in the amount of DNA during irradiation was quantified by flow cytometric analysis with propidium iodide (PI). Concurrently, we attempted a theoretical evaluation of the DNA damage by using a microdosimetric-kinetic (MK) model that was modified to incorporate the change in the amount of DNA. Our experimental results showed that the fraction of the cells in G2/M phase increased by 6.7% with 0.186 Gy/h and by 22.1% with 1.00 Gy/h after the 12th irradiation. The MK model considering the change in amount of DNA during the irradiation exhibited a higher radiosensitivity at a high dose range, which could account for the experimental clonogenic survival. The theoretical results suggest that HRS in the high dose range is associated with an increase in the total amount of DNA during irradiation.

[Role of parathyroid hormone in Klotho-FGF23 system].

Klotho was originally identified as an anti-aging gene that accelerated aging when disrupted and extended life span when overexpressed in mice. The Klotho gene encodes a single-pass transmembrane protein and is expressed in the kidney and parathyroid gland. Klotho protein functions as an obligate subunit of the receptor for fibroblast growth factor 23 (FGF23). FGF23 is a hormone secreted from osteocytes and osteoblasts and acts on renal tubular cells to promote phosphate excretion into the urine and suppress synthesis of active form of vitamin D (1,25-dihydroxyvitamin D3;1,25(OH)(2)D(3)). Decreased Klotho expression due to the kidney damage including CKD might increase the circulating level of FGF23 and trigger disturbed mineral-bone metabolism, leading to CKD-MBD. Characteristic features of CKD-MBD including hyperphosphatemia, hypocalcemia, and decreased serum 1,25(OH)(2)D(3) can be explained by (mal) adaptation of the Klotho-FGF23 system, which also contributes to the pathophysiology of secondary hyperparathyroidism (SHPT). In addition to its function as a receptor for FGF23, the extracellular domain of Klotho is secreted by ectodomain shedding and functions as a humoral factor that regulates multiple ion channels and transporters. Thus, Klotho has emerged as a key regulator of mineral metabolism in health and disease.

Accelerated recovery from Candida peritonitis of enteric origin by early surgical drainage in a peritoneal dialysis patient.

A 62-year-old man on continuous ambulatory peritoneal dialysis was transferred to our hospital with recurrent abdominal pain and a cloudy peritoneal effluent. Three weeks before the transfer, his symptoms were successfully treated with broad-spectrum antibiotics. However, their effectiveness was lost for his recurrent symptoms. Fungal peritonitis was diagnosed because of an increased white blood cell count in the peritoneal fluid on admission and isolation of Candida albicans from a peritoneal fluid culture. Intravenous fos-fluconazole was immediately started, although it was ineffective for his deteriorating symptoms. The concomitant isolation of Candida albicans in a stool culture suggested that fungal peritonitis had an enteric origin. An emergency laparotomy revealed multiple diverticulosis and sigmoid colon diverticulitis. A surgical drainage was performed in addition to peritoneal catheter removal. Postoperatively, the patient's symptoms improved rapidly and there were no signs of recurrence with continuous administration of fos-fluconazole. Surgical drainage accelerated the recovery from fungal peritonitis. This patient is the first case showing the usefulness of stool culture in the diagnosis of fungal peritonitis secondary to prior bacterial peritonitis. This case also demonstrated the importance of laparotomy to confirm the enteric origin of the fungus, and the efficacy of early surgical drainage for the treatment.