Won Seok Yang

Results on preemptive or prophylactic treatment of lamivudine in HBsAg (+) renal allograft recipients: comparison with salvage treatment after hepatic dysfunction with HBV recurrence.

Background. Lamivudine has been reported to be able to stabilize liver enzyme and hepatitis B virus (HBV) replication with recurrent hepatitis that has been regarded as a frequent and major risk factor for hepatic dysfunction and chronic liver disease in renal transplant recipients. Because large number of hepatitis antigenemia patients among renal transplant patients experience recurrent hepatic dysfunction with HBV recurrence and permanent histological deterioration, preemptive or primary prophylactic use of lamivudine before transplantation may be more beneficial than a trial for the treatment of advanced hepatic dysfunction. Methods. We conducted a double arm study to compare the efficacy of lamivudine between the preemptive (HBV DNA positive) or prophylactic (HBV DNA negative) trial for the maintenance of stable liver function (n=10) and the trial for the salvage of advanced hepatic dysfunction developed after renal transplantation (n=6) in hepatitis B viremia carrier renal transplant recipients. Results. Hepatic dysfunction with recurrent HBV antigenemia developed in 11 of 36 (30.6%) hepatitis antigenemia patients with a mean duration of 8.4 months (range 5–19.4 months). In six patients treated with lamivudine after hepatic dysfunction from recurrent hepatitis B viremia, serum AST and ALT level normalized within 1 month and HBV-DNA disappeared in all cases. HBV-DNA, however, reappeared in three (50%) without any discontinuation of lamivudine. Liver biopsy revealed recurrent chronic active hepatitis with severe activity of fibrosis in four cases, cholestatic fibrosing hepatitis in one, and permanent cirrhotic change in one. In seven patients who had preemptive lamivudine treatment at 9, 6, 2, 2, 1, 0, 0 month before the transplantation, HBV-DNA had converted to negative with a mean follow up of 1.2 months (range 1–2 month) in all case. Three patients who had prophylactic trials with lamivudine have all remained HBV-DNA negative. The recurrence rate of HBV viremia in the preemptive or prophylactic lamivudine treated group is 10.0% (1/10), which is significantly lower than that (42.3%, 11/25) in the nonlamivudine-treated group. The re-recurrence rate of HBV viremia was significantly higher (3/6, 50.0%) in the reactive lamivudine treated group than in prophylactic or preemptive group (1/10, 10%). Conclusion. Although lamivudine treatment after hepatic dysfunction can be a sound conventional treatment modality, this preliminary study may suggest that preemptive or prophylactic trial of lamivudine before hepatic dysfunction might be a more effective strategy for prevention of permanent histological deterioration and recurrence of hepatitis B viremia.

Exogenous Nitric Oxide Inhibits VCAM-1 Expression in Human Peritoneal Mesothelial Cells

Leukocyte adhesion to mesothelium is an important step during peritonitis, which is mediated by adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1). We investigated the effect of exogenous nitric oxide (NO) on VCAM-1 expression in cultured human peritoneal mesothelial cells and its signal transduction pathway. Mesothelial cells were exposed to tumor necrosis factor-α (TNF-α) in the presence or absence of NO donors, 3-morpholino-sydnonimine (SIN-1) and nitroprusside (NP). VCAM-1 mRNA and protein expression were measured by Northern blot analysis and flow cytometry. Nuclear factor-ĸB (NF-ĸB) binding activity was determined by electrophoretic mobility shift assay. Both SIN-1 and NP inhibited the TNF-α induced VCAM-1 mRNA expression in a dose dependent manner (0.25–2 mM). SIN-1 also suppressed the cell surface expression of VCAM-1 molecule. Furthermore, SIN-1 and NP inhibited the VCAM-1 mRNA expression induced by interleukin-1β or lipopolysaccharide as well. NF-ĸB inhibitor, PDTC dose dependently inhibited the TNF-α induced VCAM-1 mRNA expression. SIN-1 inhibited the TNF-α- induced NF-ĸB binding activity. Analogue of cGMP (8-bromo-cGMP) had no significant effect on TNF-α-induced VCAM-1 mRNA expression and guanylate cyclase inhibitor (ODQ) also had no significant influence on the inhibitory effect of SIN-1. These results suggest that exogenous NO inhibits VCAM-1 expression via suppression of NF-ĸB through a cGMP-independent pathway.

Treatment of hepatitis B virus associated glomerulonephritis with recombinant human alpha interferon

To evaluate the therapeutic effect of recombinant human alpha-interferon (alpha-IFN) on hepatitis B virus associated glomerulonephritis (HBV-GN) and the relationship between the seroconversion of viral antigens and the change of proteinuria, the hepatitis B viral markers and urinary protein were monitored during alpha-IFN treatment in 8 male adult patients who (1) were positive in serum HBsAg and HBeAg, (2) had chronic hepatitis, (3) had persistent proteinuria > 1 g/day, and (4) showed glomerulonephritis on kidney biopsy. alpha-IFN was given at a dose of 3 million units, subcutaneously, three times a week for 6 months. Kidney biopsy specimens showed membranoproliferative glomerulonephritis (MPGN) in 4 patients, mesangial proliferative glomerulonephritis (MesPGN) in 2, and membranous glomerulonephritis (MGN) in 2 patients. Seven of the 8 patients received a 6-month course of alpha-IFN therapy; 1 patient with MGN quitted therapy 2 months after the initial dose because of side effects. In 5 of the 7 patients who received a 6-month therapy, serum HBeAg disappeared, and anti-HBe appeared during the therapy. In 2 of these 5 patients, HBeAg reappeared, in 1 during alpha-IFN therapy and in 1 9 months after the last dose of alpha-IFN. The hepatitis B viral markers of the patient who received a 2-month therapy did not change. HBs antigenemia persisted in all patients. In all 4 patients with MPGN, serum HBeAg was transiently or persistently converted to negative, but the proteinuria persisted. Both patients with MesPGN showed remission of proteinuria; however, only 1 patient had seroconversion of HBeAg. In 2 patients with MGN, proteinuria persisted. In conclusion, alpha-IFN at the doses given was not effective in MPGN type of HBV-GN. Improvement of proteinuria was achieved in MesPGN patients without disappearance of HBs antigenemia which is the finding against the possible role of HBsAg in the pathogenesis of this type of HBV-GN.

Usefulness of Segmental Bioimpedance Ratio to Determine Dry Body Weight in New Hemodialysis Patients: A Pilot Study

Background: The ratio of bioimpedance in the right leg (rl-RBI) may be helpful in adjusting dry body weight (DBW) in new hemodialysis (HD) patients. Methods: rl-RBI was calculated as follows: rl-RBI = impedance at 50 kHz/impedance at 500 kHz, as measured by bioimpedance spectroscopy (BIS). Theoretically, rl-RBI is inversely related to extracellular water. A reference range of rl-RBI was obtained from 137 chronic but stable HD patients already achieving DBW. In 34 new HD patients (females:males = 16:18; age 49 ± 12 years), DBW(s) were stepwise adjusted under the guidance of rl-RBI by modifying the amount of ultrafiltration. Results: The target range of rl-RBI was defined as 1.106–1.150. rl-RBI before the first HD was 1.115 ± 0.027. At the study endpoint, when the target range of rl-RBI was achieved, pretibial pitting edema and pulmonary edema were resolved without any episode of muscle cramping or intradialytic hypotension. Along with an increase in rl-RBI, pre-HD blood pressure tended to decrease at systole (p = 0.072) and diastole (p = 0.005). The cardiothoracic ratio also decreased significantly (p = 0.004). Conclusion: The measurement of rl-RBI by BIS is worthy of further evaluation as an objective and applicable index for determining DBW in new HD patients.

The optimal therapy of calcineurin inhibitors for pregnancy in kidney transplantation.

We investigated the effects of pregnancy and delivery on renal function in transplant recipients and the relationship between doses of immunosuppressants and blood drug levels during pregnancy in 75 women with 88 deliveries. Significant serum creatinine elevation (> 0.5 mg/dL) was found in eight deliveries. In the remaining 80 cases, serum creatinine was reduced by an average of 0.14 mg/dL and returned to pre‐pregnant levels after delivery. Tacrolimus was used in 28 deliveries and cyclosporine in others. Tacrolimus blood trough level declined from 5.8 ± 2.8 ng/mL 12 months before delivery to 4.2 ± 1.8 ng/mL at second trimester; therefore, drug dose was increased from 4.1 ± 1.9 mg/d at first trimester to 5.5 ± 2.5 mg/d at delivery. Similarly, cyclosporine levels were 125.1 ± 65.1 ng/mL 12 months before delivery and 75.4 ± 35.0 ng/mL at second trimester resulting in dose elevation from 183.0 ± 71.8 mg/d at first trimester to 225.4 ± 85.1 mg/d at delivery. Renal function in female kidney transplant recipients improved slightly during pregnancy and returned to pre‐pregnant level after delivery. The dose elevation of calcineurin inhibitor by approximately 20–25% should be considered during gestational period to maintain optimal blood drug level.

Experiences with acute kidney injury complicating non-fulminant hepatitis A.

Aim:u2003 To describe the clinical features and to identify factors related to development of acute kidney injury in acute hepatitis A patients.

Long-term Outcomes of ABO-Incompatible Living Donor Kidney Transplantation: A Comparative Analysis

BACKGROUNDnAlthough ABO-incompatible kidney transplantation has become more common due to organ shortage, few studies on long-term outcomes have been performed in the Korean population.nnnMETHODSnA retrospective review of medical records was conducted for individuals who underwent living donor kidney transplantation at Asan Medical Center from February 2009 to January 2012.nnnRESULTSnA total of 469 patients were included; the mean age was 42.8 ± 11.8 years, and the median follow-up period was 45 (range, 1-65) months. ABO-incompatible recipients (73) were compared with ABO-compatible patients (396). Patient survival was similar between the ABO-incompatible group (97.3% and 95.9% at 1 and 3 years) and the ABO-compatible group (99.0% and 98.5% at 1 and 3 years; P = .136). Death-censored graft survival was also comparable between groups (98.6% vs 99.7% at 1 year; 98.6% vs 98.7% at 3 years; P = .386). Graft function, acute rejection, and postoperative complications were not significantly different between groups. Additionally, high body mass index and multiple human leukocyte antigen mismatches were significant risk factors for acute rejection (OR: 1.08, 95% CI: 1.01-1.16, P = .033; and OR: 1.20, 95% CI: 1.02-1.40, P = .025, respectively).nnnCONCLUSIONnABO-incompatible kidney transplantation could be a safe option when ABO-compatible donors are not available.

Exogenous Nitric Oxide Inhibits Tumor Necrosis Factor-Alpha- or Interleukin-1-Beta-Induced Monocyte Chemoattractant Protein-1 Expression in Human Mesangial Cells

Monocyte chemoattractant protein-1 (MCP-1) plays an important role in glomerulonephritis and nitric oxide (NO) exerts a variety of renal pathophysiological effects. We investigated the effect of exogenous NO on pro-inflammatory cytokine-induced MCP-1 expression in human mesangial cells and its signal transduction pathway. Cells were pretreated with NO donors such as 3-morpholino-sydnonimine (SIN-1) or nitroprusside, and then stimulated with tumor necrosis factor-α (TNF-α) or interleukin-1β (IL-1β). MCP-1 expression of mRNA and protein were measured by Northern blot analysis and ELISA. NF-ĸB binding activity was determined by electrophoretic mobility shift assay. Degradation of IĸB-α protein was assessed by Western blot analysis. SIN-1 inhibited TNF-α- or IL-1β-induced MCP-1 mRNA expression in a dose-dependent manner and also suppressed the MCP-1 protein expression. Nitroprusside inhibited the MCP-1 mRNA expression as well. SIN-1 dose dependently inhibited the TNF-α- or IL-1β-induced NF-ĸB binding activity and suppressed the TNF-α-induced degradation of IĸB-α. Analogue of cGMP (8-bromo-cGMP) had no significant effect on TNF-α-induced MCP-1 mRNA expression and guanylate cyclase inhibitor (ODQ) also had no significant influence on the inhibitory effect of SIN-1. These results suggest that exogenous NO inhibits MCP-1 expression via suppression of NF-ĸB by reducing the degradation of IĸB-α and through a cGMP-independent pathway.

Comparison of Serum Beta 2-Microglobulin and 24 hour Urinary Creatinine Clearance as a Prognostic Factor in Multiple Myeloma

A new staging system for multiple myeloma (MM) has utilized serum concentrations of beta 2-microglobulin (Sβ2M) and albumin as important prognostic factors for survival. Since Sβ2M is an indicator of glomerular filtration rate, we compared the prognostic values of Sβ2M and 24-hr urinary creatinine clearance (Ccr) in patients with MM. We retrospectively reviewed the records of 170 MM patients from January 1996 to November 2003 whose 24-hr urinary Ccr was available at the time of diagnosis. We found that pretreatment Sβ2M was inversely related to Ccr (Spearmans correlation coefficient=-0.787). In univariate analysis, the hazard ratio (HR) of death was 1.043 (p<0.001) for Sβ2M and 0.985 (p<0.001) for Ccr. Multivariate analysis showed that Sβ2M (HR 1.030, p=0.010) and Ccr (HR 0.993, p=0.059) were significant prognostic factors in patients survival. In conclusion, 24-hr urinary Ccr may be utilized for staging of patients with MM.

Low dose of mycophenolate mofetil is enough in desensitized kidney transplantation using rituximab.

BackgroundRituximab is widely used in kidney transplantation. However, it is not clear whether the conventional doses of maintenance immunosuppressant in rituximab-treated kidney transplantation (KT) are appropriate. In our previous study, decreasing mycophenolate mofetil (MMF) dose due to infection did not increase the incidence of rejection or graft failure. Based on these experiences, we developed a new protocol with a lower dose of MMF and studied its clinical outcomes in rituximab-treated KT.MethodsWe enrolled all patients who underwent ABO-incompatible or human leukocyte antigen (HLA)-sensitized living donor KT with the new immunosuppressant protocol after preconditioning with rituximab, but without splenectomy from November 2011 to May 2013. Seventy-two patients (group 1) were consecutively enrolled in this study and followed until November 2013. Patients from our previous study served as control groups. Sixty-seven patients received KT using rituximab with a conventional dose of MMF (group 2), and 87 patients received ABO compatible KT without need for rituximab (group 3). Clinical outcomes, including rejection, infection, and graft survival, were compared between the groups. The χ2 test and Fisher’s exact test were used for categorical variables, the Student’s t-test and Mann-Whitney U test were used for continuous variables, and a log-rank test was used for mortality analysis.ResultsDoses of postoperative MMF (g/day) were lower in group 1 than in the other groups (1.03u2009±u20090.19, 1.48u2009±u20090.34 and 1.48u2009±u20090.32xa0g/day at 1xa0week, pu2009<u20090.001). Infectious complications occurred more often in groups with conventional MMF doses (group 2 and 3) than in group 1 (16.7 vs. 37.3xa0%, pu2009=u20090.007 and 16.7 vs. 34.5xa0%, pu2009=u20090.012, respectively). Notably, group 1 showed a lower incidence of cytomegalovirus infection than group 2. However, reduction in MMF dose did not increase the incidence of acute rejection (4.2, 4.5 and 10.3xa0%). Only one graft failure occurred in group 2 due to vessel kinking after operation. There were no significant differences in the incidence of malignancy and mortality between groups.ConclusionsA low MMF dose reduces infection without increasing rejection or graft loss and it may be appropriate to reduce the dose of MMF for rituximab-treated KT patients.