NTx Group Research Articles

Increased Hepatocyte Growth Factor Secretion by Placenta-Derived Mesenchymal Stem Cells Improves Ovarian Function in an Ovariectomized Rat Model via Vascular Remodeling by Wnt Signaling Activation.

The vascular network contributes to the development of follicles. However, the therapeutic mechanism between vascular remodeling and ovarian functions is still unclear. Therefore, we demonstrated whether increased HGF by placenta-derived mesenchymal stem cells (PD-MSCs) improves ovarian function in an ovariectomized rat model via vascular remodeling by Wnt signaling activation. We established a half-ovariectomized rat model in which damaged ovaries were induced by ovariectomy of half of each ovary, and PD-MSCs (5 × 105 cells) were transplanted by intravenous injection. Three weeks after transplantation, rats in all groups were sacrificed. We examined the secretion of HGF by PD-MSCs through culture medium. The vascular structure in injured ovarian tissues was restored to a greater extent in the PD-MSC transplantation (Tx) group than in the nontransplantation (NTx) group (* p < 0.05). The expression of genes related to Wnt signaling (e.g., LRP6, GSK3β, β-catenin) was significantly increased in the Tx group compared to the NTx group (* p < 0.05). However, the expression of genes related to vascular permeability (e.g., Asef, ERG3) was significantly decreased in the Tx group compared to the NTx group (* p < 0.05). Follicular development was improved in the Tx group compared to the NTx group (* p < 0.05). Furthermore, to evaluate vascular function, we cocultivated PD-MSCs after human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS), and we analyzed the vascular formation assay and dextran assay in HUVECs. Cocultivation of PD-MSCs with injured HUVECs enhanced vascular formation and decreased endothelial cell permeability (* p < 0.05). Also, cocultivation of PD-MSCs with explanted ovarian tissues improved follicular maturation compared to cocultivation of the Wnt inhibitor-treated PD-MSCs with explanted ovarian tissues. Therefore, HGF secreted by PD-MSCs improved ovarian function in rats with ovarian dysfunction by decreasing vascular permeability via Wnt signaling.

Can a Large Number of Transplanted Mesenchymal Stem Cells Have an Optimal Therapeutic Effect on Improving Ovarian Function?

Mesenchymal stem cells (MSCs) are next-generation treatment in degenerative diseases. For the application of mesenchymal stem cell therapy to degenerative disease, transplantation conditions (e.g., optimized dose, delivery route and regenerating efficacy) should be considered. Recently, researchers have studied the mode of action of MSC in the treatment of ovarian degenerative disease. However, the evidence for the optimal number of cells for the developing stem cell therapeutics is insufficient. The objective of this study was to evaluate the efficacy in ovarian dysfunction, depends on cell dose. By intraovarian transplantation of low (1 × 105) and high (5 × 105) doses of placenta-derived mesenchymal stem cells (PD-MSCs) into thioacetamide (TAA)-injured rats, we compared the levels of apoptosis and oxidative stress that depend on different cell doses. Apoptosis and oxidative stress were significantly decreased in the transplanted (Tx) group compared to the non-transplanted (NTx) group in ovarian tissues from TAA-injured rats (* p &lt; 0.05). In addition, we confirmed that follicular development was significantly increased in the Tx groups compared to the NTx group (* p &lt; 0.05). However, there were no significant differences in the apoptosis, antioxidant or follicular development of injured ovarian tissues between the low and high doses PD-MSCs group. These findings provide new insights into the understanding and evidence obtained from clinical trials for stem cell therapy in reproductive systems.

Methadone use is associated with increased levels of sCD14, immune activation, and inflammation during suppressed HIV infection.

Opioid use has negative effects on immune responses and may impair immune reconstitution in persons living with HIV (PLWH) infection undergoing antiretroviral treatment (ART). The effects of treatment with μ opioid receptor (MOR) agonists (e.g., methadone, MET) and antagonists (e.g., naltrexone, NTX) on immune reconstitution and immune activation in ART-suppressed PLWH have not been assessed in-depth. We studied the effects of methadone or naltrexone on measures of immune reconstitution and immune activation in a cross-sectional community cohort of 30 HIV-infected individuals receiving suppressive ART and medications for opioid use disorder (MOUD) (12 MET, 8 NTX and 10 controls). Plasma markers of inflammation and immune activation were measured using ELISA, Luminex, or Simoa. Plasma IgG glycosylation was assessed using capillary electrophoresis. Cell subsets and activation were studied using whole blood flow cytometry. Individuals in the MET group, but no in the NTX group, had higher plasma levels of inflammation and immune activation markers than controls. These markers include soluble CD14 (an independent predictor of morbidity and mortality during HIV infection), proinflammatory cytokines, and proinflammatory IgG glycans. This effect was independent of time on treatment. Our results indicate that methadone-based MOUD regimens may sustain immune activation and inflammation in ART-treated HIV-infected individuals. Our pilot study provides the foundation and rationale for future longitudinal functional studies of the impact of MOUD regimens on immune reconstitution and residual activation after ART-mediated suppression.

Buprenorphine Naloxone and Extended Release Injectable Naltrexone for the Treatment of Opioid Use Disorder Among a Veteran Patient Sample: A Retrospective Chart Review

Objective Previous research has demonstrated the effectiveness of both extended-release injectable naltrexone (XR-NTX) and buprenorphine/naloxone (BUP-NX) in the treatment of opioid use disorder (OUD). However, studies using real-world samples with multiple medical and psychiatric comorbidities are lacking. The study’s primary aims were to: (1) compare clinical presentations in an inclusive sample of OUD-diagnosed US military veterans receiving XR-NTX and BUP-NX, and (2) investigate differences in 90-day treatment outcomes between these two groups. Methods: The medical records of 79 patients receiving medications to treat OUD in a VA hospital’s addiction outpatient treatment program were reviewed retrospectively. The analysis included all veterans who initiated medication treatment during the study period. Differences between medication groups on co-occurring diagnoses, treatment retention, and related outcomes were examined. Results: The two groups were similar in medical and psychiatric comorbidity, although the BUP-NX group were more likely to have a pain diagnosis. No statistically significant differences in retention or toxicology results were found between the two groups over the 90-day study period. The rate of positive urine screens for the BUP-NX group was 19.2% for opiates and 13.5% for other illicit substances, and 3.7% and 11.1% respectively for the XR- NTX group. Conclusion: There was no evidence that 90-days outcomes differed for veterans based on medication received, and there were more similarities than differences in clinical characteristics. Additional research is needed, including larger sample size and prospective randomized control trial to evaluate VA patients’ treatment outcomes receiving BUP-NX or XR-NTX for OUD.

Baseline N-Telopeptide Levels Correlate with Risk of Skeletal Morbidity in Patients with Multiple Myeloma during Zoledronic Acid Therapy.

BACKGROUND: Biochemical markers of bone metabolism provide valuable information about rates of bone turnover in patients with malignant bone disease. N-telopeptide of type I collagen (NTX) is released during osteolysis and is indicative of pathologic increases in bone resorption. Elevated NTX levels recently have been correlated with increased risks of skeletal-related events (SREs, defined as pathologic fracture, surgery to bone, spinal cord compression, hypercalcemia of malignancy, and the requirement for palliative radiotherapy), disease progression, and death in patients with bone metastases from solid tumors (Coleman RE, et al. J Clin Oncol. 2005; 23:4925–4935; Brown J, et al. J Natl Cancer Inst . 2005; 97:59–69).METHODS: The current univariate analysis investigated the correlation between NTX levels at baseline and SREs (including palliative radiotherapy to bone) in patients with multiple myeloma who were treated with 4 mg zoledronic acid in a phase III clinical trial (Rosen LS, et al. Cancer J. 2001; 7:377–387).RESULTS: Forty-three patients had low NTX (< 50 nmol/mmol creatinine), 45 had moderate NTX (50 to < 100 nmol/mmol creatinine), and 18 had high NTX (≥ 100 nmol/mmol creatinine) at baseline. Patients with either moderate or high NTX at baseline had significantly increased risks of on-study SREs and significantly increased risks of experiencing their first SRE while on-study compared with patients with low NTX (Table). A similar correlation was also observed for pathologic fractures alone. The risk of first events was especially high in the high NTX group. There were no significant correlations between NTX levels and the requirement for palliative radiotherapy alone.Hazard Ratios for Time to Onset and Occurrence of On-Study SRE Compared With Low (< 50 nmol/mmol creatinine) NTX (P Value)SREPathologic fracturePalliative radiotherapyBaseline NTX levelOnset of first SREAny eventOnset of first eventAny eventOnset of first eventAny eventModerate*2.76 (.012)2.26 (.003)3.78 (.001)2.98 (< .001)1.21 (.777)1.61 (.386)High†6.80 (< .001)4.01 (.001)8.87 (< .001)5.35 (< .001)3.23 (.095)3.44 (.124)*50 to < 100 nmol/mmol creatinine.; † ≥ 100 nmol/mmol creatinine.Conclusions: Multiple myeloma patients with elevated baseline NTX levels have a significantly increased risk of experiencing SREs.

Vascular remodeling by placenta-derived mesenchymal stem cells restores ovarian function in ovariectomized rat model via the VEGF pathway

AbstractAngiogenesis plays an important role in damaged organ or tissue and cell regeneration and ovarian development and function. Primary ovarian insufficiency (POI) is a prevalent pathology in women under 40. Conventional treatment for POI involves hormone therapy. However, due to its side effects, an alternative approach is desirable. Human mesenchymal stem cells (MSCs) from various sources restore ovarian function; however, they have many limitations as stem cell sources. Therefore, it is desirable to study the efficacy of placenta-derived MSCs (PD-MSCs), which possess many advantages over other MSCs, in a rat model of ovarian dysfunction. Here, we investigated the restorative effect of PD-MSCs on injured ovaries in ovariectomized (OVX) rats and the ability of intravenous transplantation (Tx) of PD-MSCs (5 × 105) to enhance ovarian vasculature and follicular development. ELISA analysis of serum revealed that compared to the non-transplantation (NTx) group, the Tx group showed significantly increased levels of anti-Müllerian hormone, follicle stimulating hormone, and estradiol (E2) (*P < 0.05). In addition, histological analysis showed more mature follicles and less atresia and restoration of expanded blood vessels in the ovaries of the OVX PD-MSC Tx group than those of the NTx group (*P < 0.05). Furthermore, folliculogenesis-related gene expression was also significantly increased in the PD-MSC Tx group (*P < 0.05). Vascular endothelial growth factor (VEGF) and VEGF receptor 2 expressions were increased in the ovaries of the OVX PD-MSC Tx group compared to the NTx group through PI3K/AKT/mTOR and GSK3β/β-catenin pathway activation. Interestingly, ex vivo cocultivation of damaged ovaries and PD-MSCs or treatment with recombinant VEGF (50 ng/ml) increased folliculogenic factors and VEGF signaling pathways. Notably, compared to recombinant VEGF, PD-MSCs significantly increased folliculogenesis and angiogenesis (*P < 0.05). These findings suggest that VEGF secreted by PD-MSCs promotes follicular development and ovarian function after OVX through vascular remodeling. Therefore, these results provide fundamental data for understanding the therapeutic effects and mechanism of stem cell therapy based on PD-MSCs and provide a theoretical foundation for their application for obstetrical and gynecological diseases, including infertility and menopause.Vascular endothelial growth factor secreted by placenta-derived mesenchymal stem cells (PD-MSCs) promotes follicular development and ovarian function after ovariectomy through vascular remodeling. These results provide fundamental data for understanding the therapeutic mechanisms of stem cell therapy based on placenta-derived mesenchymal stem cells PD-MSCs and provide a theoretical foundation for their application for obstetrical and gynecological diseases, including infertility and menopause.

Clinical outcomes of incident peritoneal dialysis patients coming from kidney transplantation program: Acase-control study.

IntroductionBrazil ranks second in the absolute number of transplantations in the world. Despite improvements in graft survival, many patients will progress to graft loss and return to dialysis. Concerns exist regarding adverse clinical outcomes in this population when undergone peritoneal dialysis (PD).ObjectiveTo compare the occurrence of mortality, technique failure, and peritonitis among incident patients in PD coming from either Tx or pre-dialysis treatment.MethodologyA retrospective study in which 47 adult patients with Tx failure (Tx group) were matched for age, gender, diabetes mellitus (DM), modality and start year of PD, with 1:1 predialysis patient (nTx group). The Fine-Gray competing risk model was used to analyze mortality and technique failure.ResultsCompared to nTx, the Tx group had a lower body mass index, serum potassium, and albumin concentrations. A higher ferritin level, transferrin saturation and the number of patients with positive serology for viral hepatitis were also observed in the Tx group. In the multivariate analysis, patients of the Tx group had 4.4-times higher risk of death (p = 0.007), with infection as the main cause. Technique failure and peritonitis were similar in both groups.ConclusionPrevious Tx is a risk factor for mortality but not for technique failure or peritonitis in incident patients on a PD program.

Effects of the hallucinogenic beverage ayahuasca on voluntary ethanol intake by rats and on cFos expression in brain areas relevant to drug addiction

Ayahuasca is a hallucinogenic infusion used in religious rituals that has serotoninergic properties and may be a potential therapeutic option for drug addiction. In this study, Wistar rats had intermittent access to ethanol for 8 weeks, receiving water (control), naltrexone (NTX, 2mg/kg body weight [bw] intraperitoneally [i.p.]) or ayahuasca (Aya) at 0.5x, 1x, or 2x the ritual dose in the final 5 days. A naïve group had access only to water. Ethanol intake was estimated throughout the experiment, and cFos expression was evaluated in medial orbital cortex (MO), ventral orbital cortex (VO), lateral orbital cortex (LO), nucleus accumbens (NAc), and striatum. Treatment with either NTX or Aya (oral) did not decrease ethanol intake compared to the baseline level (5th to 7th week), but the NTX group intake was significantly lower than controls (p<0.05). Ethanol significantly increased cFos expression in the MO region for control (p<0.0001), NTX (p<0.05), Aya1 (p<0.001), and Aya2 (p<0.0001) groups. This increase was also observed in the VO for the Aya1 group (p=0.035), in the LO for the Aya2 group (p<0.01), and in NAc for NTX and ayahuasca groups (p<0.005). Furthermore, NTX and Aya0.5 treatment decreased cFos expression compared to controls in the MO region (p<0.05 and p<0.01, respectively), but only the ayahuasca group reached levels not significantly different from the naïve group. Studies using other protocols and dose regime are necessary to better investigate the impact of ayahuasca on alcohol intake by rats to support the observations in humans. Additionally, the role of ayahuasca in mediating cFos expression in other selected brain regions and its relationship with the serotoninergic/dopaminergic systems and drug addiction need further investigation.

Efficacy and safety of telbivudine and tenofovir disoproxil fumarate in preventing hepatitis B vertical transmission: A real-life practice.

Mother-to-child transmission (MTCT) is a major obstacle in the elimination of hepatitis B virus (HBV) infection. Telbivudine (LdT) and tenofovir disoproxil fumarate (TDF) are the two most common antiviral medicines for preventing MTCT. However, the efficacy and safety of LdT and TDF in preventing HBV vertical transmission during the second to third trimester have not been compared rigorously. Therefore, we carried out a prospective multicentre cohort study of chronic hepatitis B in mothers with HBV DNA>106 IU/mL, receiving LdT or TDF during the second to third trimester. Among the 893 mothers enrolled, 857 (LdT/TDF/untreated group (NTx)=396/325/136) completed consecutive follow-up with 854 infants (LdT/TDF/NTx=395/323/136). LdT and TDF treatment resulted in a similar decrease of HBV DNA in mothers at delivery. Multivariate analysis indicated that only HBsAg titre at the baseline correlated with viral DNA decrease (P=0.015). With intention-to-treat analysis, MTCT rates in the LdT, TDF and NTx group were 4.41%, 2.42% and 22.08%, respectively. An increasing vertical transmission rate was found to be closely associated with higher HBsAg titre,5.32% and 17.65% infection rate was estimated in infants born to mothers with HBsAg>4 and >5 log10 IU/mL, respectively. No serious side effects were reported in either mothers or infants. LdT and TDF treatments were well tolerated and showed comparable efficacy in reducing MTCT. Higher risk of MTCT was shown in pregnant women with HBsAg>4 log10 IU/mL.

3D-cultured human placenta-derived mesenchymal stem cell spheroids enhance ovary function by inducing folliculogenesis

Placenta-derived mesenchymal stem cells (PD-MSCs) have numerous advantages over other adult MSCs that make them an attractive cell source for regenerative medicine. Here, we demonstrate the therapeutic effect of PD-MSCs in ovariectomized (Ovx) rats and compare their efficacy when generated via a conventional monolayer culture system (2D, naïve) and a spheroid culture system (3D, spheroid). PD-MSC transplantation significantly increased the estradiol level in Ovx rats compared with the non-transplantation (NTx) group. In particular, the estradiol level in the Spheroid group was significantly higher than that in the Naïve group at 2 weeks. Spheroid PD-MSCs exhibited a significantly higher efficiency of engraftment onto ovarian tissues at 2 weeks. The mRNA and protein expression levels of Nanos3, Nobox, and Lhx8 were also significantly increased in the Spheroid group compared with those in the NTx group at 1 and 2 weeks. These results suggest that PD-MSC transplantation can restore ovarian function in Ovx rats by increasing estrogen production and enhancing folliculogenesis-related gene expression levels and further indicate that spheroid-cultured PD-MSCs have enhanced therapeutic potential via increased engraftment efficiency. These findings improve our understanding of stem-cell-based therapies for reproductive systems and may suggest new avenues for developing efficient therapies using 3D cultivation systems.

Preoperative Serum Thymidine Kinase Activity as Novel Monitoring, Prognostic, and Predictive Biomarker in Pancreatic Cancer.

The aim of the study was to investigate serum thymidine kinase 1 (S-TK) activity as a diagnostic and prognostic marker for patients with pancreatic ductal adenocarcinoma (PDAC). Using the sensitive TK activity assay DiviTum, preoperative serum samples from 404 PDAC, 28 chronic pancreatitis, and 25 autoimmune pancreatitis patients and 83 healthy volunteers were analyzed. The preoperative S-TK activities of 54 PDAC patients who received neoadjuvant therapy (nTx) were also compared with those of 258 PDAC patients who did not receive nTx. The preoperative S-TK activities of PDAC patients were significantly higher and discriminatory from autoimmune and chronic pancreatitis patients and control groups. The S-TK activity in PDAC patients was associated with overall survival. Patients with S-TK activity of less than 80 Du (DiviTum units)/L demonstrated median survival of 20.3 months with an estimated 18.0% 5-year survival rate; for S-TK activity of 80 Du/L or greater, median survival was 15.1 months with a 6.8% 5-year survival rate. For early-stage PDAC, these differences were even more pronounced. The S-TK activity in the nTx group was significantly higher than that in the group not receiving nTx. Pancreatic ductal adenocarcinomas reveal a significant increase in S-TK activity, which is associated with overall survival, especially in early tumor stages. Serum thymidine kinase 1 activity may be a useful parameter for monitoring nTx efficacy.

PP14.7 – 2997: Screening osteoporosis in patients with antiepileptic drug using urine N-telopeptide of collagen type I

Objective Antiepileptic drug (AED) can affect bone metabolism. But pediatric neurologists ignore the fact because of shorter use of AED in children than in adults. We tried to find out results of reduced bone mineral density (BMD) after use of AED and appropriate screening methods for osteoporosis. Methods This retrospective study was conducted in total 63 patients with epilepsy who visit the Department of Pediatrics of Catholic University Bucheon Saint Mary's Hospital from January 2013 to December 2014. We measure BMD by dual photon absorptiometry and check urine N-telopeptide of collagen type I (NTx) level for bone turnover marker. Results In whole study population, 37 urine NTx level elevated higher than normal range. Among positive urine NTx group, 17 patients had results of reduced BMD after use of AED. Patients with valproic acid (VPA) were 18, oxcarbazepine (OCZ) 28, levetiracetam (LEV) 26, topiramate (TPM) 9 and lamotrigine (LTG) 8. Due to preceding number including multidrug therapy cases, patients with single VPA were 9, single OCZ 19, single LEV 8, single TPM 0 and single LTG 0. Positive urine NTx number of VPA, OCZ, LEV, TPM and LTG group was 9, 21 (P=0.02), 12, 5 and 4 respectively. Positive urine NTx number single VPA, single OCZ and single LEV group was 4, 16 (P=0.01) and 3 respectively. Conclusion Some patient had reduced BMD after use of AED. The incidence of positive urine NTx was significantly different between the patients with OCZ and those with other AEDs in both monotherapy and multitherapy. We suggest using urine NTx for bone turnover marker in pediatric patients with AED.

Text-messaging program improves outcomes in outpatient cardiovascular rehabilitation

BackgroundOutpatient cardiac rehabilitation (OP-CR) is a highly beneficial program but vastly under utilized. MethodsThe efficacy of a text-messaging program was analyzed to determine if implementation could improve number of OP-CR sessions completed. All patients enrolled in OP-CR from July 2011 through December 2012 were invited to join a text-messaging program on their first visit. The program required that the patient possesses a cell phone with texting capabilities. Participants received three to five text-messages per week offering heart-healthy tips and requests for body weight, minutes of exercise, blood pressure, and medication adherence. Patients enrolled (n=52) in the texting program (Tx) were compared with those who were not (n=185) (NTx) in several clinical indices and were compared using matched pairs (same subjects), comparison of means and frequencies, chi-square statistics, t-tests, and the Wilcoxon Rank Sum test. ResultsSignificantly more patients in the Tx group completed the OP-CR program (61.5% versus 50%, p=0.01). For those completing OP-CR, subjects in the Tx group completed significantly more sessions (31.4) than the NTx group (25.3) (p=0.01). Additionally, significantly more in the Tx group were younger than those in the Ntx group. ConclusionsPatients enrolled in OP-CR who participated in a text-messaging program were younger, attended significantly more sessions and were significantly more likely to complete the program.

Telbivudine or lamivudine use in late pregnancy safely reduces perinatal transmission of hepatitis B virus in real-life practice.

Little observational data exist describing telbivudine (LdT) or lamivudine (LAM) use in late pregnancy for preventing hepatitis B mother-to-child transmission (MTCT) in real-world settings. During the period of January 2009 to March 2011, we enrolled hepatitis B e antigen–positive mothers with HBV DNA >6 log10 copies/mL in China. At gestation week 28, the mothers received LdT or LAM until postpartum week 4 or no treatment (NTx). The study endpoints were the safety of LdT/LAM use and MTCT rates. Of the 700 mothers enrolled, 648 (LdT/LAM/NTx = 252/51/345) completed the 52-week study with 661 infants (LdT/LAM/NTx = 257/52/352). On treatment, viral rebound occurred in 1.6% of mothers, all resulting from medication noncompliance. There was no genotypic mutation detected. At delivery, significantly lower HBV DNA levels were noted in mothers who received LdT or LAM versus NTx. Alanine aminotransferase flares were observed in 17.1% of treated mothers versus 6.3% of untreated mothers (P < 0.001). At birth, hepatitis B surface antigen (HBsAg) was detected in 20% and 24% of newborns in the treated and NTx groups, respectively. At week 52, an intention-to-treat analysis indicated 2.2% (95% confidence [CI]: 0.6-3.8) of HBsAg+ infants from the treated group versus 7.6% (95% CI: 4.9-10.3) in the NTx group (P = 0.001) and no difference of HBsAg+ rate between infants in the LdT and LAM groups (1.9% vs. 3.7%; P = 0.758). On-treatment analysis indicated 0% of HBsAg+ infants in the treated group versus 2.84% in the NTx group (P = 0.002). There were no differences for gestational age or infants' height, weight, Apgar scores, or birth defect rates between infants from the treated and untreated groups. Conclusions: LdT and LAM use in late pregnancy for highly viremic mothers was equally effective in reducing MTCT. The treatment was well tolerated with no safety concerns identified.

Analysis of Histologic Changes During Early Rejection After Renal Transplantation by Performing Protocol Biopsy at 1 Year After Kidney Transplantation

BackgroundIn this retrospective study, we analyzed histologic changes identified through protocol biopsy (PB) at 1 year after kidney transplantation (KT). We focused on the pathologic changes observed in patients with a history of treatment for graft rejection within 1 year of transplantation. MethodsBetween January 2008 and December 2011, 56 patients underwent KT at our center. We assessed the histologic findings observed at 1 year after renal transplantation using the Banff 2007 classification. At our center, PBs are performed immediately after or at 1 hour after transplantation, and at 1 year after KT. PBs were performed in 39 patients; PBs could not be performed in 17 patients because of various causes. Of the 39 patients, 29 stabilized without clinical rejection and without treatment (the NTx group); 10 patients showed pathologic changes or clinical rejection after steroid pulse therapy within 1 year (the Tx group). We compared these 2 groups with respect to baseline data, renal function, and pathologic scores. ResultsThe interstitial fibrosis (“ci”) score, according to the Banff classification, was significantly greater in the NTx group (0.89) than in the Tx group (0.50) at 1 year after transplantation. ConclusionsThe currently applied early steroid withdrawal regimen may be not be ideal for preventing pathologic changes occurring after KT. In addition to the PB performed 1 year after KT, PB should be performed within 1 year of renal transplantation to identify early signs of rejection and to provide access to appropriate treatment regimes.

An Angiotensin Converting Enzyme Inhibitor Suppresses Contrast Media Induced Renal Dysfunction in a Murine Model of Subtotal Nephrectomy

Backgrounds: Contrast media (CM)-induced nephropathy (CIN) affects morbidity and mortality in humans. Although CIN is mediated by several factors including the renin-angiotensin system (RAS), little is known about the pathophysiology. To clarify the mechanism, we developed a novel murine CIN model. Methods: We made 5/6 subtotal nephrectomy (NTX) and administered CM (iopamidol) intravenously into the mice 4 weeks after NTX. Mice received an angiotensin converting enzyme inhibitor (ACEI, n=6), an angiotensin II receptor blocker (ARB, n=4), or ACEI plus a bradykinin B2 receptor antagonist (Hoe-140, n=5) daily. Results: Serum creatinine levels were significantly elevated in the NTX group compared to the non-NTX group on day 28. A day after CM injection, creatinine levels were additionally elevated in the non-treated group. While ACEI treatment significantly suppressed the creatinine levels, ARB treatment did not decrease the levels. Hoe-140 negated ACEI’s ability to suppress renal dysfunction. Conclusion: ACEI treatment may be useful for the prevention of CM-induced nephropathy. Keywords: Angiotensin converting enzyme, bradykinin, contrast media, murine model, renal dysfunction, renin angiotensin system.

Stepwise Treatment Using Corticosteroids Alone and in Combination with Cyclosporine in Korean Patients with Idiopathic Membranous Nephropathy

PurposeWe undertook an observational study to investigate the effects of immunosuppressive treatment on proteinuria and renal function in 179 Korean idiopathic membranous nephropathy patients with nephrotic syndrome.Materials and MethodsThe primary outcome was regarded as the first appearance of remission and the secondary outcomes as a decline in estimated glomerular filtration rate (eGFR) >50% or initiation of dialysis, and all-cause mortality. Seventy-two (40.2%) and 50 (27.9%) patients were treated with corticosteroids alone (C) and corticosteroids plus cyclosporine (C+C), respectively, whereas 57 (31.8%) did not receive immunosuppressants (NTx). Cyclosporine was added if there was no reduction in proteinuria of >50% from baseline by corticosteroids alone within 3 months.ResultsThere were no differences in baseline renal function and the amount of proteinuria among the three groups. Overall, complete remission (CR) was achieved in 88 (72.1%) patients by immunosuppressants. In a multivariate analysis adjusted for covariates associated with adverse renal outcome, the probability of reaching CR was significantly higher in the C [hazard ratio (HR), 4.09; p<0.001] and C+C groups (HR, 2.57; p=0.003) than in the NTx group. Kaplan-Meier analysis revealed that 5-year CR rates of C, C+C, and NTx groups were 88.5%, 86.2%, and 56.7% (p<0.001). Ten-year event-free rates for the secondary endpoints in these three groups were 91.7%, 79.9%, and 57.2% (p=0.01).ConclusionImmunosuppressive treatment was effective in inducing remission and preserving renal function in these patients. Therefore, stepwise treatment using corticosteroids alone and in combination with cyclosporine is warranted in these patients.

Skeletal-related Events and Clinical Outcomes in Patients with Bone Metastases and Normal Levels of Osteolysis: Exploratory Analyses

AimsHigh levels of bone resorption markers (e.g. N-telopeptide of type I collagen; NTX) have been correlated with increased risks of skeletal-related events and death in patients with bone metastases from solid tumours. However, the disease course has not been well characterised in patients with bone metastases but normal NTX levels. Therefore, the aim of this study was to evaluate the patterns of skeletal morbidity in patients with normal NTX levels. Materials and methodsExploratory analyses were carried out on patients with bone metastases from breast cancer, castration-resistant prostate cancer, non-small cell lung cancer or other solid tumours treated with zoledronic acid (ZOL) in phase III trials. The effects of covariates on the relative risk of death were estimated using the Cox proportional hazard model. The prognostic values of covariates were compared between patients with normal (<64 nmol/mmol creatinine) versus elevated (≥64 nmol/mmol creatinine) NTX levels. ResultsAmong patients with normal baseline NTX (n = 501), less than 10% developed elevated NTX levels before a skeletal-related event or death during ZOL treatment over 12 months. The prognostic factors identified in these analyses were mostly similar across NTX groups. However, some indicators of aggressive disease (e.g. visceral/cerebral metastases from breast cancer) were associated with poor clinical outcomes only in the normal NTX group. ConclusionsSkeletal-related events were generally not preceded or followed by transition to elevated NTX in patients treated with ZOL. Elevated baseline NTX and aggressive extraskeletal disease were independently associated with reduced survival.

Chronic allograft injury by subclinical borderline change: evidence from serial protocol biopsies in kidney transplantation

PurposeThis study investigated the impact of subclinical borderline changes on the development of chronic allograft injury in patients using a modern immunosuppression protocol.MethodsSeventy patients with stable renal allograft function and who underwent protocol biopsies at implantation, 10 days and 1 year after transplantation were included and classified based on biopsy findings at day 10. The no rejection (NR) group included 33 patients with no acute rejection. The treatment (Tx) group included 21 patients with borderline changes following steroid pulse therapy, and the nontreatment (NTx) group included 16 patients with borderline changes nontreated.ResultsThe Banff Chronicity Score (BChS) and modified BChS (MBChS) were not different among the three groups at implantation (P = 0.48) or on day 10 (P = 0.96). Surprisingly, the NTx group had more prominent chronic scores at the 1-year biopsy, including BChS (3.07 ± 1.33, P = 0.005) and MBChS (3.14 ± 1.41, P = 0.008) than those in the Tx and NR group, and deterioration of BChS was more noticeable in the NTx group (P = 0.037), although renal function was stable (P = 0.66). No difference in chronic injury scores was observed between the Tx and NR groups at the 1-year biopsy.ConclusionSubclinical borderline changes can be a risk factor for chronic allograft injury and should be considered for antirejection therapy.

Abstract 5268: A Critical Role of Bradykinin in the Murine Model of Contrast Media-Induced Nephropathy

Background: Iodinated contrast media (CM) has been broadly used for diagnostic procedures; CM-induced nephropathy (CIN) affects morbidity and mortality of patients. Although CIN is known to be mediated by several factors, including the renin-angiotensin system (RAS), little is known about the evidence obtained from experimental models. Thus, we developed a murine CIN model to evaluate the mechanism. Methods: We performed 5/6 subtotal nephrectomy (NTX) and administered CM (iopamidol, 500 μ l/25 g mice) intravenously into the mice 4 weeks after NTX. We administered an angiotensin converting enzyme inhibitor (ACEI, imidapril, 1 mg/kg/day, n=6), an angiotensin II receptor blocker (ARB, TA606, 1 mg/kg/day, n=4), or ACEI plus a bradykinin B2 receptor antagonist (Hoe-140, 0.25 mg/kg, n=5) into the mice daily. Results: Serum creatinine levels on day 28 were significantly elevated in the NTX group (0.26±0.01 mg/dl) compared to those in the non-NTX group (0.13±0.01 mg/dl). A day after CM injection, creatinine levels were significantly elevated in the non-treated group (0.41±0.01 mg/dl). While ACEI treatment significantly suppressed the increase in creatinine levels (0.34±0.04 mg/dl, p&lt;0.05 vs. CIN group), ARB treatment did not suppress (0.47±0.06 mg/dl). A bradykinin antagoninst Hoe-140 negated (0.43±0.07 mg/dl, p&lt;0.05 vs. CIN+ACEI) ACEI’s ability to suppress renal damage. We examined renal AT1R, COX-2, MCP-1 and MMP-9 mRNA levels using quantitative RT-PCR. AT1R mRNA levels were enhanced in the NTX and CIN groups compared to those in the native group. COX-2, MCP-1 and MMP-9 mRNA levels were enhanced in the CIN+ACEI group compared to the native and CIN groups. ACEI+Hoe-140 treatment suppressed the mRNA expression. Both treatments did not reduce their blood pressure compared to those of the vehicle treatment, statistically. Conclusion: ACEI treatment is useful for the prevention of CM-induced nephropathycompared to that of ARB treatment in the murine model of CIN because bradykinin pathway is critical in regulating CIN development.