Ji-Young Choi

Successful withdrawal of antiviral treatment in kidney transplant recipients with chronic hepatitis B viral infection.

The optimal duration of antiviral therapy for kidney transplant recipients (KTR) with chronic hepatitis B virus (HBV) infection remains unclear. We reported the long‐term outcomes after withdrawal of antiviral agent in KTR with chronic HBV infection.

Systemic and Local Impact of Glucose and Glucose Degradation Products in Peritoneal Dialysis Solution

The main osmotic agent used in the peritoneal dialysis (PD) solution is glucose because of its great osmotic power, simple metabolism, and safety. Once into the systemic circulation, however, glucose can be a cause for metabolic complications including hyperglycemia, obesity, and dyslipidemia. The glucose absorbed from peritoneal cavity leads to insulin resistance and hyperglycemia, which is associated with oxidative stress. Long-term exposure of peritoneal membrane to glucose in PD solution also has local effects such as functional and structural changes leading to peritoneal membrane failure. Moreover, the intraperitoneal glucose absorption induces conditions similar to postprandial hyperglycemia, which is a proven independent risk factor of coronary artery disease in patients with type 2 diabetes. Though speculative, glucose toxicity might explain a higher mortality of PD patients after the first few years compared with those on hemodialysis. Glucose degradation products (GDPs) induce apoptosis of peritoneal mesothelial cells (PMCs), renal tubular epithelial cells, and endothelial cells, and facilitating epithelial mesenchymal transition of PMCs. GDPs provide a stronger reactivity than glucose in the formation of advanced glycation end-products, a known cause for microvascular complications and arteriosclerosis. Unfortunately, clinical studies using a low-GDP PD solution have provided mixed results on the residual renal function, peritonitis, peritoneal membrane function, and mortality; consistent outcome data are not readily available at present.

Interleukin‐18, transforming growth factor‐β, and vascular endothelial growth factor gene polymorphisms and susceptibility to primary glomerulonephritis

Several studies have showed an association of gene polymorphisms with the development of glomerulonephritis (GN). We investigated the effects of gene polymorphisms on the development of GN by analyzing polymorphisms in the interleukin (IL)-18, transforming growth factor (TGF)-β, and vascular endothelial growth factor (VEGF) genes in Korean patients with primary GN. The study included 146 normal subjects (controls) and 100 patients diagnosed with primary GN by kidney biopsy. The gene polymorphisms A-607C and G-137C in IL-18, C-509T and T869C in TGF-β1, and C-2578A and C405G in VEGF were investigated in DNA extracted from peripheral blood. Significant differences were observed between the GN and control groups in the genotype and allele frequencies of A-607C IL-18 and C405G VEGF. The frequencies of the IL-18-607CC genotype [P = 0.001, odds ratio (OR) = 2.473] and the VEGF 405GG genotype (P = 0.001, OR = 2.473) were significantly increased in the GN group. The combination of IL-18-607CC+ and VEGF 405GG+ genotypes had a higher risk for developing GN in comparison with the combination of IL-18-607CC- and VEGF 405GG- genotypes (P < 0.001, OR = 8.642). In the haplotype analysis of the IL-18 gene, the CG haplotype was significantly more frequent in the GN group than the control group (61.5% vs 46.9%, P = 0.002). These results show that the -607CC genotype of the IL-18 gene and the 405GG genotype of the VEGF gene are associated with susceptibility to and the development of primary GN.

Hypoxanthine induces cholesterol accumulation and incites atherosclerosis in apolipoprotein E-deficient mice and cells.

Reactive oxygen species (ROS) generation during purine metabolism is associated with xanthine oxidase and uric acid. However, the direct effect of hypoxanthine on ROS generation and atherosclerosis has not been evaluated. Smoking and heavy drinking are associated with elevated levels of hypoxanthine. In this study, we investigated the role of hypoxanthine on cholesterol synthesis and atherosclerosis development, particularly in apolipoprotein E (APOE)‐deficient mice. The effect of hypoxanthine on the regulation of cholesterol synthesis and atherosclerosis were evaluated in Apoe knockout (KO) mice and cultured HepG2 cells. Hypoxanthine markedly increased serum cholesterol levels and the atherosclerotic plaque area in Apoe KO mice. In HepG2 cells, hypoxanthine increased intracellular ROS production. Hypoxanthine increased cholesterol accumulation and decreased APOE and ATP‐binding cassette transporter A1 (ABCA1) mRNA and protein expression in HepG2 cells. Furthermore, H2O2 also increased cholesterol accumulation and decreased APOE and ABCA1 expression. This effect was partially reversible by treatment with the antioxidant N‐acetyl cysteine and allopurinol. Hypoxanthine and APOE knockdown using APOE‐siRNA synergistically induced cholesterol accumulation and reduced APOE and ABCA1 expression. Hypoxanthine induces cholesterol accumulation in hepatic cells through alterations in enzymes that control lipid transport and induces atherosclerosis in APOE‐deficient cells and mice. These effects are partially mediated through ROS produced in response to hypoxanthine.

Effect of DNA Demethylation in Experimental Encapsulating Peritoneal Sclerosis

Encapsulating peritoneal sclerosis (EPS) involves excessive peritoneal fibrosis in patients on peritoneal dialysis, eventually leading to visceral constriction and bowel obstruction. Few studies have investigated epigenetic mechanisms relating to EPS. Here we evaluated the therapeutic effects of DNA demethylation in experimental EPS. Experimental EPS was induced by intraperitoneal injection of 0.1% chlorhexidine gluconate (CG) and 15% ethanol in non‐uremic male Sprague–Dawley (SD) rats. Rats were divided into three groups: group C (Nu2009=u20095) with saline injection only, group CG (Nu2009=u20097) with EPS induction for 4u2009weeks, and chlorhexidine gluconate and azacytidine (CGA) treated group (Nu2009=u20097) with EPS induction for 4u2009weeks and 5‐azacytidine injection for the last 2u2009weeks. Morphometric analysis of peritoneum and immunohistochemical staining for type 1 collagen and α‐smooth muscle actin (α‐SMA) were performed. Expressions of transforming growth factor‐β (TGF‐β), fibroblast‐specific protein 1 (FSP1), and DNA methyltransferase 1 (DNMT1) were analyzed by Western blot. Methylation‐specific polymerase chain reaction (PCR) for Ras GTPase activating‐like protein 1 (RASAL1) was performed with measurement of RASAL1 protein expression. Parietal peritoneal thickness and the number of vessels in omental tissue were significantly decreased in group CGA compared to group CG, as were the expressions of type 1 collagen, α‐SMA, TGF‐β, and FSP1. DNMT1 was significantly increased in group CG, and reduced in group CGA. RASAL1 hypermethylation was associated with decreased RASAL1 protein expression in group CG, which was reversed in group CGA. DNA demethylation by 5‐azacytidine treatment improved pathologic changes of the peritoneum in experimental EPS, and was associated with reversal of increased DNMT1 expression and RASAL1 hypermethylation.

Impact of gene polymorphisms of interleukin-18, transforming growth factor-β, and vascular endothelial growth factor on development of IgA nephropathy and thin glomerular basement membrane disease

Background We investigated the effects of gene polymorphisms on the development of IgA nephropathy and thin glomerular basement membrane (GBM) disease by analyzing polymorphisms in the interleukin (IL)-18, transforming growth factor (TGF)-β, and vascular endothelial growth factor (VEGF) genes in Korean patients. Methods This study included 146 normal individuals and 69 biopsy-proven IgA nephropathy and 44 thin GBM disease patients. The gene polymorphisms −607 A/C and −137 G/C in IL-18, −509C/T and T869C in TGF-β, and −2578C/A and 405C/G in VEGF were investigated in DNA extracted from peripheral blood. Results The frequencies of the IL-18 −607CC genotype (43.5% vs. 21.2%, P=0.002, P corrected=0.012) and the VEGF 405 GG genotype (37.7% vs. 21.2%, P=0.002, P corrected=0.012) were significantly increased in the IgA nephropathy group compared with the control group, whereas no significant differences in genotype frequency were observed between the thin GBM disease and control groups. However, there were no significant differences in genotype and allele frequencies between the IgA nephropathy and thin GBM disease groups. Conclusion This study did not show any statistically significant differences of six selected gene polymorphisms of the IL-18, TGF-β, and VEGF genes between IgA nephropathy and thin GBM disease. Additional extensive studies are required to clarify the potential role of gene polymorphism to discriminate IgA nephropathy and thin GBM disease without renal biopsy.

A Case of Transient Central Diabetes Insipidus after Aorto-Coronary Bypass Operation

Diabetes insipidus (DI) is characterized by excessive urination and thirst. This disease results from inadequate output of antidiuretic hormone (ADH) from the pituitary gland or the absence of the normal response to ADH in the kidney. We present a case of transient central DI in a patient who underwent a cardiopulmonary bypass (CPB) for coronary artery bypass grafting (CABG). A 44-yr-old male underwent a CABG operation. An hour after the operation, the patient developed polyuria and was diagnosed with central DI. The patient responded to desmopressin and completely recovered five days after surgery. It is probable that transient cerebral ischemia resulted in the dysfunction of osmotic receptors in the hypothalamus or hypothalamus-pituitary axis during CPB. It is also possible that cardiac standstill altered the left atrial non-osmotic receptor function and suppressed ADH release. Therefore, we suggest that central DI is a possible cause of polyuria after CPB.

Characteristics and Clinical Significance of De Novo Donor-Specific Anti-HLA Antibodies after Kidney Transplantation

Background The association of de novo donor-specific anti-human leukocyte antigens (HLA) antibodies (DSA) and development of antibody-mediated rejection (AMR) in kidney transplant recipients (KTRs) is still undetermined. Methods We prospectively screened de novo DSA in 167 KTRs during 32 months after kidney transplantation (KT). Timing of DSA detection was at 3, 6, and 12 months post-transplant and annually thereafter and when clinically indicated. DSA levels were determined by Luminex assays and expressed as mean fluorescence intensity (MFI). We evaluated the incidence, characteristics of DSA, and association between DSA and tacrolimus trough levels or AMR. Results De novo DSA developed in 16 KTRs (9.6%) and acute AMR occurred more commonly in KTRs with de novo DSA compared to KTRs without de novo DSA (18.8% vs. 0%, P < 0.001). All de novo DSA were against class II antigens. The mean number of DSA was 1.8 ± 1.2 and the average MFI of DSA was 7,399 ± 5,470. Tacrolimus trough level during the first 0–2 months after KT was an independent predictor of DSA development (hazard ratio, 0.70; 95% confidence interval, 0.50–0.99; P = 0.043). No differences were found in the number of DSA, average MFI of DSA, and tacrolimus levels during the first year between de novo DSA-positive KTRs with AMR and those without AMR. Conclusion The results of our study suggest that monitoring of DSA and maintaining proper tacrolimus levels are essential to prevent AMR during the initial period after KT.

Usefulness of mycophenolic acid monitoring with PETINIA for prediction of adverse events in kidney transplant recipients

Abstract Background Therapeutic drug monitoring of mycophenolic acid (MPA) is required to optimize the immunosuppressive effect and minimize toxicity. We validated a new particle-enhanced turbidimetric inhibition immunoassay (PETINIA) for the determination of MPA levels and evaluated the relationship of MPA trough level with drug-related adverse events. Methods PETENIA and liquid chromatography-mass spectrometry (LC-MS) were used to determine MPA concentrations from 54 kidney transplant recipients (KTRs). Agreement between PETINIA and LC-MS results was assessed by Passing-Bablok regression and the Bland-Altman plot method. The association of adverse events with MPA trough level obtained by PETINIA was analyzed. Results PETINIA revealed a good agreement with the LC-MS; Regression analysis gave an equation of yu2009=u20091.27xu2009−u20090.12 (r2u2009=u20090.975, pu2009<u20090.001). PETINIA showed a systemic positive bias with a mean difference of 0.66u2009mg/L compared to LC-MS. However, the magnitude of the positive bias decreased to 0.44u2009mg/L within the therapeutic range of MPA. Multiple logistic regression showed that MPA trough level determined by PETINIA was an independent risk factor for adverse events (odds ratio 2.28, 95% CI 1.25–4.16, pu2009=u20090.007). MPA trough level predicted adverse events with a sensitivity of 77.8% and a specificity of 86.7% using a cut-off level of 5.25u2009mg/L. Conclusions Good correlation between the two methods indicates that PETINIA is an acceptable method for the monitoring of MPA therapeutic levels. Furthermore, MPA trough level obtained by PETINIA is a useful monitoring tool to minimize toxicity in KTRs.

Exceptional mucocutaneous manifestations with amyloid nephropathy: a case report

BackgroundAmyloidosis is a very rare disease that is difficult to diagnose because of the unspecific early clinical manifestations of the disease. Accurate and early diagnosis is extremely important because the effect of treatment is dependent on the extent of disease progression. Sicca syndrome and nail dystrophy are very rare symptoms of amyloidosis. We report here a case of sicca syndrome and nail dystrophy with renal dysfunction in a 52-year-old Korean woman who was diagnosed as having systemic amyloidosis.Case presentationWe present the case of a 52-year-old Korean woman complaining of dry mouth and nail dystrophy for 4 months as an initial symptom. A slit lamp examination revealed superficial keratoconjunctival erosion in both eyes. A laboratory test showed anemia, azotemia, and proteinuria. Urine protein electrophoresis showed increased gamma globulin excretion. Serum free light chain of kappa and lambda were increased. Histopathological studies of biopsy specimens of minor salivary glands and kidney revealed deposits of amyloid fibrils. A bone marrow aspiration biopsy showed hypercellular marrow with 5% plasma cells. She was diagnosed as having primary systemic amyloidosis then started on chemotherapy.ConclusionSuch atypical mucocutaneous manifestations of amyloidosis can serve as important early diagnostic signs with less invasive biopsy confirmation in patients with systemic amyloidosis.