Changes in body composition and low blood urea nitrogen level related to an increase in the prevalence of fatty liver over 20 years: A cross-sectional study.

AIM: Qualitative body composition (BC) change, characterized by the combination of visceral fat gain and muscle loss, is drawing attention as a risk factor for fatty liver (FL). The present study aimed to describe trends in BC change and its association with FL in the Japanese population. METHODS: Data from medical checkups carried out on 56 639 Japanese participants every 5 years from 1997 to 2017 were analyzed. Fat mass index (FMI) and fat-free mass index (FFMI) were calculated using body mass index and body fat percentage. Subjects were divided into two groups according to deviations from the correlation line of FMI and FFMI as the reference: FMI-predominant BC and FFM-dominant BC. Fatty liver was determined using abdominal ultrasonography. RESULTS: The prevalence of FL significantly increased from 27.3% to 42.7% in men and from 18.0% to 25.5% in women. The prevalence of FMI predominance significantly increased from 33.6% to 43.9% in men and from 29.1% to 47.0% in women. Fat mass index predominance was independently associated with FL in men and women (odds ratio: 1.96 and 1.94, respectively). Serum blood urea nitrogen level was inversely associated with FL in men and women (0.958 and 0.961, respectively) and significantly decreased from 15.8 to 14.9 mg/dl in men and from 15.1 to 14.0 mg/dl in women. CONCLUSIONS: Increasing FMI-predominant BC and decreasing serum blood urea nitrogen level could account for the increase in the prevalence of FL over 20 years. We believe that these factors stem from current lifestyle habits in Japan.

Impact of acute kidney injury on prognosis and the effect of tolvaptan in patients with hepatic ascites.

BACKGROUND: In hepatic cirrhosis, ascites and acute kidney injury (AKI) portend poor prognosis. We examined the incidence and characteristics of AKI in patients with hepatic ascites and the impact of diuretics on AKI onset. METHODS: This study included 337 patients with hepatic ascites treated with oral diuretics during September 2013-June 2019. Incidence of AKI, cumulative survival by AKI status, and prognostic factors were investigated. Patients were divided into those treated with tolvaptan (TLV) [TLV group (n = 244)] and those not treated with TLV [control group (n = 93)]. After propensity score matching, the incidence of AKI and changes in renal function and doses of diuretics were compared. RESULTS: The incidence of AKI overall was 35% (n = 118). Patients with AKI had a significantly worse survival than those without AKI (P = 0.001), indicating that AKI is an independent prognostic factor for hepatic ascites (P = 0.025). After adjustment for background factors in the two groups (n = 77 each), the TLV group had a significantly lower incidence of AKI (27.6% vs. 44.7%, P = 0.028). While renal function worsened with higher natriuretic agent doses in the control group, no significant change was observed in the TLV group, suggesting that TLV is an independent prognostic factor for AKI onset. CONCLUSIONS: Our study suggests that concomitant AKI significantly worsens survival in Japanese patients with hepatic ascites, and TLV and natriuretic agent combination therapy might lead to an excellent synergistic therapeutic effect of hepatic ascites and inhibition of AKI onset.

Association between bone mineral density, muscle volume, walking ability, and geriatric nutritional risk index in hemodialysis patients.

BACKGROUND AND OBJECTIVES: Hemodialysis patients are at risk for bone loss and sarcopenia, characterized by reduced muscle mass and limited mobility/function. Osteoporosis and sarcopenia both increase the risk of hospitalization and death in affected individuals. Malnutrition also occurs as a complication of hemodialysis and has been identified as a risk factor for osteoporosis and sarcopenia. In this study, we examined the relationship between osteoporosis, muscle volume, walking ability, and malnutrition in hemodialysis patients. METHODS AND STUDY DESIGN: Forty-five hemodialysis patients were evaluated. Bone mineral density (BMD) and muscle volume were measured by dual-energy X-ray absorptiometry. Muscle volume and strength were evaluated using lean mass index (LMI), handgrip strength, and walking ability. The time required for a patient to walk 10 meters was measured to evaluate walking ability. The geriatric nutritional risk index (GNRI) was used to assess malnutrition. RESULTS: Multiple linear regression analysis showed that older age, female sex, lower LMI, and higher total type I procollagen N-terminal propeptide were correlated with lower BMD of lumbar spine. Higher age and lower LMI were correlated with lower BMD of the femoral neck. Female sex and lower GNRI were correlated with lower LMI. Longer duration of hemodialysis was correlated with lower walking ability. CONCLUSIONS: Our findings suggest that muscle preservation is required to maintain both lumbar spine and femoral neck BMD. Similarly, nutritional management is necessary to maintain BMD via preservation of muscle volume. Complementary nutritional therapies are needed to improve osteoporosis and sarcopenia in high-risk hemodialysis patients.

[A case of renal Fanconi syndrome due to Bence Jones' protein K-type multiple myeloma].

A 60-year-old man, who had been treated for chronic kidney disease and chronic hepatitis B infection, was referred to our hospital following presentation with thoracic bone pain and exacerbation of proteinuria and hematu- ria. On admission, laboratory test results showed evidence of hypophosphatemia, glucosuria and elevated levels of both urinary NAG and 62MG.The patient was diagnosed with Fanconi syndrome based on findings indicating the presence of pan-aminoaciduria, elevated urinary excretion of uric acid and an increased phosphorus reabsorption rate. Furthermore, bone scintigraphy showed increased multiple symmetric uptake of radiotracer in both sides of the ribs, leading to the diagnosis"of hypoposphatemia-related osteomalacia with renal Fanconi syndrome. Urinary immunoelectrophoresis indicated the presence of K Bence Jones' protein (BJP). A bone marrow biopsy examina- tion showed that the plasma-to-cell ratio was less than 10%. However, the patient had over lg/day of proteinuria and suppression of serum IgM (18mg/dL) and was, therefore, diagnosed with multiple myeloma based on SWOG criteria. Light microscopic examination showed evidence of glomerulosclerosis, intimal thickness of interlobular arteries and acidophilic granular deposits in the cytoplasm of the proximal epithelial tubular cells. Immunofluores- cence indicated positive anti-K staining in these regions. Electron microscopic examination of the proximal tubular epithelial cells revealed the presence of numerous diamond-shaped and oval crystals, thought to be the K light chain of BJP. In general, cast nephropathy, light chain deposition disease (LCDD) and AL amyloidosis are recog- nized renal injuries caused by myeloma. However, there have been few clinical reports of Fanconi syndrome with multiple myeloma, such as the case study we have described here. In addition, histological examination of a biopsy sample provided further evidence of K BJP in the proximal epithelial tubular cells.

Correlation of serum levels of complement C4a desArg with pathologically estimated severity of glomerular lesions and mesangial hypercellularity scores in patients with IgA nephropathy.

The aim of the present study was to explore serum biomarkers for the pathology of IgA nephropathy using serum proteomics. The subjects were 57 patients with IgA nephropathy who were divided into two groups (group 1, n=25; group 2, n=32) and 14 healthy controls. Serum protein profiles were analyzed using the ProteinChip surface-enhanced laser desorption ionization (SELDI) system. Associations between signal intensities of proteins and histological findings in patients with IgA nephropathy were studied in group 1. Serum levels of a candidate biomarker protein (complement component C4a desArg) for IgA nephropathy were determined by enzyme linked-immunosorbent assay (ELISA) in group 2 and the relationships of these levels with histological findings were evaluated. There were significant differences in 93 protein signals between patients in group 1 and controls. Among these signals, 3 proteins at 8592, 8757 and 8806 m/z were significantly correlated with the severity of glomerular lesions. The protein at 8592 m/z was identified as C4a desArg and the signal intensity of 8592 m/z was strongly correlated with serum C4a levels, including C4a desArg, determined by ELISA. In addition, the serum levels of C4a (mainly C4a desArg) were significantly higher in patients in group 2 compared to controls and were correlated with the severity of glomerular lesions and with mesangial hypercellularity scores. In conclusion, the serum levels of complement C4a desArg are significantly higher in patients with IgA nephropathy compared to healthy controls and are significantly correlated with the severity of glomerular lesions and mesangial hypercellularity scores. Thus, serum C4a desArg is a potential biomarker for the severity of histological findings in patients with IgA nephropathy.

High serum thioredoxin levels are reduced after tonsillectomy in patients with IgA nephropathy.

OBJECTIVE: The role of oxidative stress in IgA nephropathy (IgAN), the most common type of primary glomerulonephritis, is unknown. We evaluated the clinical significance of serum levels of oxidative stress markers, thioredoxin (TRX) and manganese superoxide dismutase (MnSOD), in patients with IgAN. METHODS: Forty-eight patients with histologically confirmed IgAN and 14 healthy subjects were enrolled in this study. Serum samples from 14 IgAN patients were obtained after tonsillectomy, a procedure hypothesized to be an effective treatment for IgAN. RESULTS: Serum TRX levels were significantly higher in patients with IgAN than in healthy subjects (mean [ng/mL]; 49.5 vs.14.4, p<0.001). Serum TRX levels are positively correlated with blood urea nitrogen, serum uric acid and proteinuria, and negatively with estimated glomerular filtration rate (eGFR). In addition, serum TRX levels gradually increased as the severity of renal histology increased. High levels of serum TRX were significantly decreased after tonsillectomy in patients with IgAN (mean [ng/mL]; 55.5 to 41.1, p=0.02). In contrast, serum MnSOD levels did not differ between IgAN patients and healthy subjects, and these levels did not change after tonsillectomy in IgAN patients. CONCLUSION: Serum TRX is associated with IgAN, and tonsillectomy may decrease oxidative stress in IgAN patients, leading to clinical improvement.

Hepatocyte growth factor sustains T regulatory cells and prolongs the survival of kidney allografts in major histocompatibility complex-inbred CLAWN-miniature swine.

BACKGROUND: Although 12 days of high dose of FK506 permits the induction of tolerance of fully major histocompatibility complex (MHC)-mismatched allogeneic kidneys in MGH-miniature swine, we found that the same dose of FK506 is insufficient to induce such tolerance CLAWN-miniature swine. The CLAWN swine model was therefore chosen to study the potential immunoregulatory effects of human-recombinant hepatocyte growth factor (HGF). METHODS: Ten CLAWN miniature swine received fully MHC-mismatched kidneys with 12 days (days 0-11) of FK506. Among these 10 recipients, 4 received 7 or 14 days of human-recombinant HGF starting at day 11. Graft function was assessed by daily serum creatinine and biopsies. Immunologic assays, including CD4/CD25 DP and FoxP3+ cells and development of antidonor antibodies, were performed. RESULTS: Without HGF, all six CLAWN recipients developed severe acute rejection (Cre >9 mg/dL) within 3 weeks of transplantation. In contrast, in the four animals that received HGF for 7 to 14 days, stable renal function was observed for more than 50 days, although all grafts were ultimately rejected by postoperative day 80. Percent FoxP3+ cells in the CD4+CD25+ double positive population (T regulatory cells) in peripheral blood monocyte cells decreased in recipients with FK506 induction monotherapy while no reduction was observed in recipients treated with FK506 and HGF. CONCLUSION: This study demonstrates that in CLAWN swine treated with a dose of FK506 insufficient to induce tolerance across a fully MHC mismatched barrier, a short course of HGF may inhibit acute rejection while maintaining T regulatory cells. To our knowledge, this study provides the first evidence in a large animal transplantation model of HGF's immunoprotective effects.

Human neutrophil peptide-1 aggravates dextran sulfate sodium-induced colitis.

BACKGROUND: Human neutrophil peptide (HNP)-1, HNP-2, and HNP-3 (HNP-1-3) are useful biomarkers for ulcerative colitis (UC). The precise roles of these peptides in UC are poorly understood, however. The aim of this study was to determine whether HNP-1 affects disease activity in mice with experimental colitis. METHODS: Experimental colitis was induced in BALB/c or severe combined immunodeficiency (SCID) mice using dextran sulfate sodium (DSS). Mice were subsequently treated intraperitoneally with HNP-1 (100 µg/day) or phosphate-buffered saline (PBS) from day 4 to day 6. The severity of colitis was evaluated based on a disease activity index, histologic score, and cytokine expression. RESULTS: Body weight and colon length significantly decreased and the disease activity index score, histologic score, and myeloperoxidase activity significantly increased in HNP-1-treated BALB/c mice compared with PBS-treated mice. Interferon-γ and tumor necrosis factor-α levels in colon culture supernatants-derived HNP-1-treated mice were also significantly higher, and interleukin (IL)-1ß levels tended to increase in response to HNP-1. In addition, treating SCID mice with HNP-1 aggravated DSS-induced colitis and IL-1ß levels in colon culture supernatants from these mice were significantly higher than in cultures obtained from control mice. Furthermore, in both BALB/c and SCID mice increased recruitment of F4/80-positive macrophages was observed in the inflamed colonic mucosa following HNP-1 injections. CONCLUSIONS: High concentrations of HNP-1 aggravate DSS-induced colitis, including upregulated expression of such macrophage-derived cytokines as IL-1ß. These results indicate that high concentrations of HNP-1-3 in patients with UC may exacerbate disease activity via increased cytokine production.

Beneficial effects of perioperative low-dose inhaled carbon monoxide on pulmonary allograft survival in MHC-inbred CLAWN miniature swine.

BACKGROUND: We have recently reported that perioperative low-dose carbon monoxide (CO) inhalation decreases lung ischemia-reperfusion injury in miniature swine. The aims of this study were to establish a large animal model of pulmonary allograft rejection using polymerase chain reaction-typed major histocompatibility complex (MHC)-inbred CLAWN miniature swine and to examine the effects of CO on allograft survival. METHODS: Eleven CLAWN miniature swines received fully MHC-mismatched lungs followed by 12 days of tacrolimus (days 0-11; blood level 35-45 ng/mL). Six recipients received tacrolimus alone (control group). Five recipients were additionally treated with inhaled CO (180 min for donors until graft harvest; 390 min for recipients until 2 hr after reperfusion). RESULTS: All recipients treated with tacrolimus alone uniformly rejected their grafts by postoperative day 63 with development of cytotoxic antidonor antibodies. CO treatment was effective in prolonging allograft survival from a mean of 47±7 to 82±13 days (P=0.017), with one CO-treated animal maintaining function until postoperative day 120. Development of antidonor antibodies and donor-specific responsiveness by cell-mediated lympholysis and mixed lymphocyte reaction assays was delayed in animals that received CO therapy. Furthermore, serum concentrations of proinflammatory cytokines (interleukin-1ß and -6) 1 day after transplant were significantly decreased in the CO-treated group. CONCLUSIONS: Fully MHC-mismatched lungs in CLAWN miniature swine were consistently rejected within 63 days, suggesting that this is a robust large animal model ideal for investigating mechanisms and treatment of lung rejection. Perioperative low-dose CO inhalation prolonged graft survival and inhibited antidonor antibody production and was associated with decreased proinflammatory mediators in this model.

Insulin-like growth factor binding protein-1 levels are increased in patients with IgA nephropathy.

The mechanisms underlying the pathogenesis of immunoglobulin A (IgA) nephropathy (IgAN) are not well understood. In this study, we examined gene expression profiles in kidneys obtained from mice with high serum IgA levels (HIGA mice), which exhibit features of human IgAN. Female inbred HIGA, established from the ddY line, were used in these experiments. Serum IgA levels, renal IgA deposition, mesangial proliferation, and glomerulosclerosis were increased in 32-week-old HIGA mice in comparison to ddY animals. By microarray analysis, five genes were observed to be increased by more than 2.5-fold in 32-week-old HIGA in comparison to 16-week-old HIGA; these same five genes were decreased more than 2.5-fold in 32-week-old ddY in comparison to 16-week-old ddY mice. Of these five genes, insulin-like growth factor (IGF) binding protein (IGFBP)-1 exhibited differential expression between these mouse lines, as confirmed by quantitative RT-PCR. In addition, serum IGFBP-1 levels were significantly higher in patients with IgAN than in healthy controls. In patients with IgAN, these levels correlated with measures of renal function, such as estimated glomerular filtration rate (eGFR), but not with sex, age, serum IgA, C3 levels, or IGF-1 levels. Pathologically, serum IGFBP-1 levels were significantly associated with the severity of renal injury, as assessed by mesangial cell proliferation and interstitial fibrosis. These results suggest that increased IGFBP-1 levels are associated with the severity of renal pathology in patients with IgAN.

Carbon monoxide reduces pulmonary ischemia-reperfusion injury in miniature swine.

OBJECTIVES: Carbon monoxide is produced endogenously as a by-product of heme catalysis and has been shown to reduce ischemia-reperfusion injury in a variety of organs in murine models. The aims of this translational research were to establish an in situ porcine lung model of warm ischemia-reperfusion injury and to evaluate the cytoprotective effects of low-dose inhaled carbon monoxide in this model. METHODS: Warm ischemia was induced for 90 minutes by clamping the left pulmonary artery and veins in 8 Clawn miniature swine (Japan Farm CLAWN Institute, Kagoshima, Japan). The left main bronchus was also dissected and reanastomosed just before reperfusion. Four animals were treated with inhaled carbon monoxide at a concentration of approximately 250 ppm throughout the procedure. Lung function and structure were serially accessed via lung biopsy, chest x-ray films, and blood gas analysis. RESULTS: Carbon monoxide inhalation dramatically decreased the lung injury associated with ischemia and reperfusion. Two hours after reperfusion, the arterial oxygen tension of the carbon monoxide-treated group was 454 +/- 34 mm Hg, almost double the arterial oxygen tension of the control group (227 +/- 57 mm Hg). There were fewer pathologic changes seen on chest x-ray films and in biopsy samples from animals in the carbon monoxide-treated group. Animals in the carbon monoxide-treated group also had fewer inflammatory cell infiltrates and a markedly smaller increase in serum concentrations of the proinflammatory cytokines interleukin 1beta, interleukin 6, and high-mobility group box 1 after ischemia-reperfusion injury. CONCLUSIONS: The perioperative administration of low-dose inhaled carbon monoxide decreases warm ischemia-reperfusion injury in lungs in miniature swine. This protective effect is mediated in part by the downregulation of proinflammatory mediators.

Clinical significance of alanine aminotransferase levels and the effect of ursodeoxycholic acid in hemodialysis patients with chronic hepatitis C.

BACKGROUND: The natural history of hepatitis C virus (HCV) carriers and the effect of ursodeoxycholic acid (UDCA) have not been fully elucidated among hemodialysis (HD) patients. METHODS: Eighty-four anti-HCV antibody- and HCV RNA-positive and 154 anti-HCV antibody-negative HD patients who were retrospectively observed for at least 3 years were analyzed. We investigated the factors associated with thrombocytopenia (< 1.3 x 10(5)/microL) and decreased platelet count (PLT) (more than 20% decrease during the follow-up period), which were considered to be indicators of hepatic fibrosis. In addition, another 16 HD patients with HCV who received 300 mg/day UDCA orally for at least 6 months were investigated. Changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT) and PLT were assessed. RESULTS: After the 60.3-months mean follow-up period, HCV infection was independently associated with both thrombocytopenia [odds ratio (OR) 2.589] and decreased PLT (OR 2.339) in 238 HD patients. In 84 HD patients with HCV, the average ALT levels (> or = 15 IU/L) during the follow-up period was associated with thrombocytopenia (OR 3.882) and decreased PLT (OR 4.470). In addition, ALT, AST and GGT significantly decreased at 6 months after starting UDCA, but PLT did not change in 16 HD patients with HCV. CONCLUSIONS: These results indicate that HCV infection is a risk for thrombocytopenia which should be associated with hepatic fibrosis in HD patients. In addition, the clinical course of ALT levels predicts the progression of thrombocytopenia, and UDCA may effectively lower ALT levels in HD patients with HCV.

Porcine CFSE mixed lymphocyte reaction and PKH-26 cell-mediated lympholysis assays.

UNLABELLED: Mixed lymphocyte reaction (MLR) and cell-mediated lympholysis (CML) are widely used to assess T cell responses. A major limitation of the traditional MLR and CML assays is that they require radioisotope labeling with (3)H for MLR and (51)Cr for CML, thereby limiting their use to laboratories with the capabilities to deal safely with these materials. Recently, flow cytometry with CFSE labeling has been used to detect cell division in rodent and human assays, and flow cytometry with PKH-26 labeling has been used to study cytotoxicity in murine models. Partially inbred miniature swine provide a unique large animal preclinical model for experimental transplantation, helping to bridge the gap between rodent and clinical studies. In this study, we modified the reported CFSE and PKH-26 labeling procedures for use with porcine cells, and established that these radioactive-free MLR and CML assays are comparable to traditional radioactive CML and MLR assays for assessing immunologic responses in miniature swine. To our knowledge, this is the first report that has directly compared the traditional CML/MLR with radiation-free CML/MLR in MHC-defined swine models. OBJECTIVE: The aim of this study is to establish non-radiolabeled CSFE and PKH-26 labeling procedures for flow cytometry based CML/MLR assays that are comparable to radioactive CML/MLR assays in preclinical large animals.