Optimizing Surveillance Performance of Alpha-Fetoprotein by Selection of Proper Target Population in Chronic Hepatitis B.

Although alpha-fetoprotein (AFP) is the most widely used biomarker in hepatocellular carcinoma (HCC) surveillance, disease activity may also increase AFP levels in chronic hepatitis B (CHB). Since nucleos(t)ide analog (NA) therapy may reduce not only HBV viral loads and transaminase levels but also the falsely elevated AFP levels in CHB, we tried to determine whether exposure to NA therapy influences AFP performance and whether selective application can optimize the performance of AFP testing in CHB during HCC surveillance. A retrospective cohort of 6,453 CHB patients who received HCC surveillance was constructed from the electronic clinical data warehouse. Covariates of AFP elevation were determined from 53,137 AFP measurements, and covariate-specific receiver operating characteristics regression analysis revealed that albumin levels and exposure to NA therapy were independent determinants of AFP performance. C statistics were largest in patients with albumin levels ≥ 3.7 g/dL who were followed without NA therapy during study period, whereas AFP performance was poorest when tested in patients with NA therapy during study and albumin levels were < 3.7 g/dL (difference in C statics = 0.35, p < 0.0001). Contrary to expectation, CHB patients with current or recent exposure to NA therapy showed poorer performance of AFP during HCC surveillance. Combination of concomitant albumin levels and status of NA therapy can identify subgroup of CHB patients who will show optimized AFP performance.

Off-treatment virologic relapse and outcomes of re-treatment in chronic hepatitis B patients who achieved complete viral suppression with oral nucleos(t)ide analogs.

BACKGROUND: The durability of off-treatment virologic responses has not been fully elucidated in chronic hepatitis B (CHB) patients who have previously achieved complete virologic suppression with nucleos(t)ide analog (NA) therapy. This study aimed to assess off-treatment virologic relapse rates and to characterize the outcomes of subsequent re-treatment in CHB patients who have discontinued oral NA following complete virologic suppression. METHODS: Ninety-five CHB patients who showed complete virologic suppression were withdrawn from NAs: entecavir, lamivudine, and clevudine in 67, 15, and 13 patients, respectively. Consolidation therapy was given for 6 and 12 months for HBeAg-positive and -negative CHB, respectively, before cessation. Virologic relapse was managed with the same NA that had induced complete virologic response before discontinuation. RESULTS: The cumulative rates of virologic relapse at 12 and 24 months were 73.8% and 87.1%, respectively. The relapse rates were independent of HBeAg positivity, HBeAg seroconversion, and type of oral NA. In a multivariate analysis, duration of oral NA therapy was the only significant predicting factor associated with off-treatment virologic relapse. Although the majority of patients regained complete virologic suppression, some patients did not respond to re-treatment with the initial NA and developed genotypic resistance. CONCLUSIONS: NA consolidation therapy for 6 and 12 months is associated with high off-treatment virologic relapse in HBeAg-positive and -negative CHB patients, respectively. Drugs with high genetic barriers to resistance should be considered as a rescue therapy for off-treatment relapse in CHB.

Pretreatment serum HBsAg-to-HBV DNA ratio predicts a virologic response to entecavir in chronic hepatitis B.

BACKGROUND/AIMS: Decay of hepatitis B surface antigen (HBsAg) titers has previously been shown to be predictive of a virologic response (VR), especially during peginterferon-alpha therapy. However, the role of HBsAg levels in predicting a VR to nucleos(t)ide analog therapy has not yet been established. In this study we sought to determine whether the VR can be predicted from HBsAg titers in nucleos(t)ide-naive chronic hepatitis B (CHB) patients treated with entecavir. METHODS: CHB patients who started entecavir as an initial antiviral therapy were enrolled in this study. Serum hepatitis B virus (HBV) DNA, HBsAg, and alanine aminotransferase levels were measured every 3 months during treatment. A VR was defined as undetectable serum HBV DNA titer by real-time PCR assay (<60 IU/mL). RESULTS: Fifty-two patients were enrolled, and the median duration of treatment was 26 months (range 7-35 months). Forty-five patients achieved a VR; the cumulative VR rates at 3, 6, 12, and 24 months were 40%, 71.2%, 81.5%, and 88%, respectively. Baseline HBV DNA levels were significantly lower in patients with VR, whereas the HBsAg levels did not differ significantly between patients with or without VR. In a univariate analysis the cumulative VR rate was significantly higher in HBeAg negative patients and patients with an HBsAg/HBV DNA ratio above 0.56. However, in a multivariate analysis only an HBsAg/HBV DNA ratio above 0.56 was an independent predictor of VR (P=0.003). The area under the receiver operating characteristic curve was larger for the HBsAg/HBV DNA ratio than for either HBV DNA or HBsAg. CONCLUSIONS: Pretreatment HBsAg/HBV DNA ratio can predict a long-term VR to entecavir therapy in nucleos(t)ide-naive CHB patients.

The first case of genotype 4 hepatitis E related to wild boar in South Korea.

Several cases of serologically diagnosed hepatitis E have been reported in South Korea; however, there have been no documented cases of zoonotic transmission with virologic characterization of hepatitis E virus (HEV). We report on a sporadic case of autochthonous acute hepatitis E after ingestion of raw bile juice obtained from a wild boar living on a domestic mountain in a southern part of Korea. It is the first case of hepatitis E acquired through presumably zoonotic transmission, which was verified as genotype 4 HEV.

Endoscopic subureteral polydimethylsiloxane injection and prevention of recurrent acute graft pyelonephritis.

BACKGROUND/AIMS: Vesicoureteral reflux (VUR) is an important factor in recurrent acute graft pyelonephritis (AGPN). In this study, we evaluated the effect of subureteral polydimethylsiloxane (PDS) injection on recurrent AGPN in renal transplant recipients with VUR. METHODS: 64 renal transplant recipients with recurrent AGPN were included, 31 (48%) of whom had VUR. Of the patients with VUR, 19 (61%) were treated with PDS and the others were managed with antibiotics. The effect of PDS treatment on recurrent AGPN was evaluated in terms of the overall success rate, the success rate according to VUR grade, and the number of PDS treatments. RESULTS: The overall success rate of PDS injection was 63%, and the number of AGPN episodes was significantly reduced after injection compared with the number before injection (0.21 vs. 1.34 times/person-year, respectively, p < 0.05). The success rate of PDS treatment differed with the VUR grade (50% in grade 1, 33% in grade 2, 75% in grade 3, and 67% in grade 4). The success rate in the first trial was 67% and in the second it was 50%. CONCLUSION: PDS injection is an effective treatment for recurrent AGPN in renal allograft recipients with VUR.

[Comparison between conventional 4 L polyethylene glycol and combination of 2 L polyethylene glycol and sodium phosphate solution as colonoscopy preparation].

BACKGROUND/AIMS: Effective bowel preparation is essential for accurate diagnosis of colon disease. We investigated efficacy and safety of 2 L polyethylene glycol (PEG) solution with 90 mL sodium phosphate (NaP) solution compared with 4 L PEG method. METHODS: Between August 2009 and April 2010, 526 patients were enrolled who visited Seoul National University Bundang Hospital for colonoscopy. We allocated 249 patients to PEG 4 L group and 277 patients to PEG 2 L with NaP 90 mL group. Detailed questionnaires were performed to investigate compliance, satisfaction and preference of each method. Bowel preparation quality and segmental quality were evaluated. Success was defined as cecal intubation time less than 20 minutes without any help of supervisors. RESULTS: Both groups revealed almost the same baseline characteristics except the experience of operation. PEG 4 L group's compliance was lower than PEG 2 L with NaP 90 mL group. Success rate and cecal intubation time was not different between two groups. Overall bowel preparation quality of PEG 2 L with NaP 90 mL group was better than PEG 4 L group. Segmental bowel preparation quality of PEG 2 L with NaP 90 mL group was also better than PEG 4 L group in all segments, especially right side colon. Occurrence of hyperphosphatemia was higher in PEG 2 L with NaP 90 mL group than PEG 4 L group. However, significant adverse event was not reported. CONCLUSIONS: PEG 2 L with NaP 90 mL method seems to be more effective bowel preparation than PEG 4 L method.

Predictors for progression in immunoglobulin A nephropathy with significant proteinuria.

AIM: Proteinuria is a primary factor requiring treatment in immunoglobulin (Ig)A nephropathy. The purpose of this study was to assess the relevance of treatment response and relapse of proteinuria with renal function decline. METHODS: One hundred and twenty-five biopsy-proven primary IgA nephropathy patients who had more than 1.0 g/day proteinuria at the first assessment were studied. All patients underwent anti-proteinuric treatment, and the association of the rate of renal function decline with treatment responsiveness, clinical and laboratory data was investigated. RESULTS: The treatment response of the patients was: 30.4% complete response (<0.3 g/day proteinuria), 32.8% partial response (0.3-1.0 g/day), 23.2% minimal response (decrement but not reduced to <1 g/day) and 13.6% no response (no decrement of proteinuria). The slope of renal function decline (-1.06 vs-1.24 mL/min per 1.73 m(2)/year, P = 0.580) was comparable between complete and partial response groups, but they were slower than those of minimal or non-response groups (P < 0.001). In multivariate analysis including other parameters, mean arterial pressure (MAP; beta = -0.240, P = 0.004) during follow up, minimal (beta = -0.393, P < 0.001) and non-response (beta = -0.403, P < 0.001) were significant predictors. In further investigation of complete and partial response groups, MAP (beta = -0.332, P = 0.001) and relapse of proteinuria (beta = -0.329, P = 0.001) were independently associated with slope of renal decline. CONCLUSION: Achievement of less than 1.0 g/day proteinuria and MAP were important for limiting the loss of renal function, and relapse of proteinuria should be closely monitored in proteinuric IgA nephropathy.

The efficacy and safety of ezetimibe and low-dose simvastatin as a primary treatment for dyslipidemia in renal transplant recipients.

BACKGROUND/AIMS: The efficacy and safety of a combination of ezetimibe and low-dose statin as primary treatment for dyslipidemia in renal transplant patients were evaluated prospectively. METHODS: The study enrolled 77 renal transplant recipients with dyslipidemia. They were given ezetimibe (10 mg) and simvastatin (10 mg) for 6 months as the initial treatment for dyslipidemia. Efficacy and safety were evaluated using lipid profiles, trough calcineurin inhibitor levels, allograft function, and adverse effects. The effects on proteinuria and high sensitivity C-reactive protein (hsCRP) levels were also evaluated. RESULTS: Ezetimibe and low-dose simvastatin significantly decreased the levels of total cholesterol (34.6%), triglyceride (16.0%), and low-density lipoprotein cholesterol (LDL-C) (47.6%), and 82.5% of the patients reached the target LDL-C level of <100 mg/dL. No significant change in the trough calcineurin inhibitor levels or allograft function occurred, and no serious adverse effects were observed. Fourteen patients (18.2%) discontinued treatment; eight patients (11.7%) developed muscle pain or weakness without an increase in creatinine kinase levels, and two patients (2.6%) developed elevated liver transaminase levels. The proteinuria and hsCRP levels did not change significantly. CONCLUSIONS: Ezetimibe and low-dose statin treatment is safe and effective as a primary treatment for dyslipidemia in renal transplant patients.

Comparison of long-term outcomes between spousal transplants and other living unrelated donor transplants: single-center experience.

BACKGROUND/AIMS: The greater use of living unrelated donors (LUDs) as kidney donors is a worldwide trend in the current era of organ shortage, and spouses are an important source of LUDs. This study was to compare the long-term outcomes of spousal donor grafts with other LUD grafts. METHODS: Among 445 LUD grafts, 77 were spouses and 368 were other LUDs. The clinical characteristics and long-term survival rates for spousal transplants were compared with those for other LUD transplants, and risk factors affecting graft survival were assessed. RESULTS: Spousal donors had a significantly higher average number of human leukocyte antigen (HLA) mismatches (4.2 vs. 3.4, p < 0.001) and were older (41 vs. 33 years, p < 0.001) than LUDs. The 10-year survival rates for spousal donor grafts were 60.6%, similar to those for LUD grafts (58.5%, p = 0.61). The 10-year biopsy-proven acute rejection-free survival rates (85.5 vs. 89.6%, p = 0.45) and patient survival rates were also similar (84.3 vs. 79.6%, p = 0.35). The degree of HLA mismatching, the spousal donor type or donor age did not affect the graft survival. CONCLUSION: Renal transplants from spousal donors show similar long-term outcomes to those from better HLA-matched and younger LUDs.

Successful renal transplantation with desensitization in highly sensitized patients: a single center experience.

Intravenous immunoglobulin (IVIG) and/or plasmapheresis (PP) are effective in preventing antibody-mediated rejection (AMR) of kidney allografts, but AMR is still a problem. This study reports our experience in living donor renal transplantation in highly sensitized patients. Ten patients with positive crossmatch tests or high levels of panel-reactive antibody (PRA) were included. Eight patients were desensitized with pretransplant PP and low dose IVIG, and two were additionally treated with rituximab. Allograft function, number of acute rejection (AR) episodes, protocol biopsy findings, and the presence of donor-specific antibody (DSA) were evaluated. With PP/IVIG, six out of eight patients showed good graft function without AR episodes. Protocol biopsies revealed no evidence of tissue injury or C4d deposits. Of two patients with AR, one was successfully treated with PP/IVIG, but the other lost graft function due to de novo production of DSA. Thereafter, rituximab was added to PP/IVIG in two cases. Rituximab gradually decreased PRA levels and the percentage of peripheral CD20+ cells. DSA was undetectable and protocol biopsy showed no C4d deposits. The graft function was stable and there were no AR episodes. Conclusively, desensitization using PP/IVIG with or without rituximab increases the likelihood of successful living donor renal transplantation in sensitized recipients.

Combined effects of losartan and pravastatin on interstitial inflammation and fibrosis in chronic cyclosporine-induced nephropathy.

BACKGROUND: Statins and angiotensin II type I receptor blockers have synergistic effects on vascular smooth-muscle-cell proliferation and the progression of renal diseases. We evaluated whether combined treatment with losartan (LSRT) and pravastatin (PRVT) affords superior protection compared with their respective monotherapies in treating chronic cyclosporine (CsA)-induced nephropathy in rats. METHODS: Rats maintained on a low salt diet were given vehicle, CsA (15 mg/kg), CsA and LSRT (10 mg/kg), CsA and PRVT (5 mg/kg), or a combination of CsA, LSRT, and PRVT for 28 days. Basic parameters (renal function, systolic blood pressure, serum high-sensitivity C-reactive protein [hs-CRP], and lipid profiles), histopathology (arteriolopathy, tubulointerstitial fibrosis, and inflammatory cell infiltration), and inflammatory and fibrotic factors (intrarenal CRP, angiotensin II, osteopontin, and transforming growth factor [TGF]-beta1) were studied. RESULTS: LSRT or PRVT treatment significantly attenuated the histopathologic changes induced by CsA, and combined treatment with LSRT and PRVT further decreased these parameters compared with giving each drug alone. Increased levels of angiotensin II, intrarenal CRP, osteopontin, and TGF-beta1 in CsA-treated rat kidney were reduced by treatment with either LSRT or PRVT and were further decreased by the combination of the two drugs. There were no significant differences in systolic blood pressure or serum lipid parameters between groups. CONCLUSIONS: Combined treatment with LSRT and PRVT provided synergistic effects in attenuating inflammatory and fibrotic processes in a rat model of chronic CsA-induced nephropathy, and this effect was independent of their hypolipidemic and hypotensive actions.

Non-Hodgkin's lymphoma manifest as gingival hyperplasia in a renal transplant recipient.

Gingival hyperplasia is a frequent complication in transplant patients who receive cyclosporine or calcium channel blockers. We studied an unusual case involving a renal transplant recipient with post-transplant non-Hodgkin's lymphoma that manifested as gingival hyperplasia. We initially consider that it was a side effect of cyclosporine and nifedipine. The lesion did not respond to dose reductions or the withdrawal of cyclosporine and nifedipine, and the gingival hyperplasia progressed in a localized fashion, becoming ulcerated and bleeding easily. Histological examination revealed the presence of malignant lymphoma.