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1.  Pretransplant malnutrition, inflammation, and atherosclerosis affect cardiovascular outcomes after kidney transplantation 
BMC Nephrology  2015;16:109.
Background
Malnutrition, inflammation, and atherosclerosis (MIA) syndrome is associated with a high mortality rate in patients with end-stage renal disease. However, the clinical relevance of MIA syndrome in kidney transplantation (KT) recipients remains unknown.
Methods
We enrolled 1348 adult KT recipients. Recipients were assessed based on serum albumin, cholesterol, or body mass index for the malnutrition factor and C-reactive protein level for the inflammation factor. Any history of cardiovascular (CV), cerebrovascular, or peripheral vascular disease satisfied the atherosclerosis factor. Each MIA factors were assessed by univariate analysis and we calculated an overall risk score by summing up scores for each independent variable. The enrolled patients were divided into 4 groups depending on the MIA score (0, 2–4, 6, 8–10).
Results
The patients with higher MIA score showed worse outcome of fatal/non-fatal acute coronary syndrome (ACS) (p < 0.001) and composite outcomes of ACS and all-cause mortality (p < 0.001) than with the lower MIA score. In multivariate analysis, ACS showed significantly higher incidence in the MIA score 8-10 group than in the MIA score 0 group (Hazard ratio 6.12 95 % Confidence interval 1.84–20.32 p = 0.003).
Conclusions
The presence of MIA factors before KT is an independent predictor of post-transplant CV outcomes.
doi:10.1186/s12882-015-0108-3
PMCID: PMC4508766  PMID: 26194096
Acute Coronary Syndrome; Atherosclerosis; Cardiovascular Outcome; Inflammation; Kidney Transplantation; Malnutrition
2.  Increased urinary Angiotensinogen/Creatinine (AGT/Cr) ratio may be associated with reduced renal function in autosomal dominant polycystic kidney disease patients 
BMC Nephrology  2015;16:86.
Background
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary kidney diseases that frequently result in renal failure. In this cross-sectional observational cohort study, we evaluated urinary angiotensinogen (AGT) as a potential biomarker to assess renal function in ADPKD.
Methods
Urinary AGT was measured in 233 ADPKD patients and its association with estimated glomerular filtration rate (eGFR) and height-adjusted total kidney volume (htTKV) were evaluated. The localization of AGT and other renin-angiotensin system (RAS)-related molecules were identified using immunohistochemistry in human ADPKD tissues.
Results
Baseline urinary AGT/Cr was negatively correlated with CKD-EPI eGFR (r2  = 0.162, P < 0.001) and positively correlated with htTKV (r2 = 0.107, P < 0.001). Both urinary AGT/Cr and plasma renin activity levels were significantly elevated in hypertensive ADPKD patients. Among hypertensive subjects, urinary AGT/Cr was significantly increased in the advanced CKD stages (III-V) compared to early CKD stages (I-II) (28.6 ± 60.3 vs. 93.2 ± 139.3 μg/g, P < 0.001). Immunohistochemical study showed strong expression of AGT along the cyst-lining epithelial cells as well as the nearby compressed tubular epithelial cells.
Conclusions
Our results suggested that urinary AGT/Cr may be a valuable biomarker for renal damage in ADPKD since intrarenal ischemic insults induced by cyst growth and subsequent intrarenal RAS activation may play a potential role in the development of hypertension and renal dysfunction in ADPKD.
Electronic supplementary material
The online version of this article (doi:10.1186/s12882-015-0075-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12882-015-0075-8
PMCID: PMC4475321  PMID: 26092580
Angiotensinogen; Autosomal dominant polycystic kidney disease; Biomarkers; Renal function; Renin-angiotensin system
3.  Availability of Empty Zona Pellucida for Generating Embryonic Chimeras 
PLoS ONE  2015;10(4):e0123178.
In the present study we used an empty zona pellucida derived from hatched blastocysts as an alternative source for embryo aggregation and compared results with the conventional microwell method. Denuded 4-cell stage porcine embryos were aggregated by introduction into an empty zona or placement within a concave microwell. The present study showed that although the rate of aggregate formation was similar, the blastocyst rates and allocation of more cells to the inner cell mass (ICM) in the resultant aggregates were increased significantly more in the empty zona than in the microwell. Notably, using an empty zona showed no limitations with regards to the increased number of embryos aggregated or embryonic stages for aggregation, while partial or no aggregation frequently occurred in the microwell. The discrepancy may be due to the difference of microenvironments where the embryos were placed namely, the presence/absence of zona pellucida. We hypothesize the success of the empty zona in generating aggregates is due to the physical aggregation of individual embryos allowing closer contact between the blastomeres and/or embryos compared with a concave microwell. These results indicate that aggregation conditions could influence overall production efficiency and developmental potential of aggregates, suggesting physical restraint via empty zona that provide three-dimensional pressures is an important factor for successful embryo aggregation.
doi:10.1371/journal.pone.0123178
PMCID: PMC4412630  PMID: 25919298
5.  Environmental Heavy Metal Exposure and Chronic Kidney Disease in the General Population 
Journal of Korean Medical Science  2015;30(3):272-277.
Lead (Pb), mercury (Hg), and cadmium (Cd) are common heavy metal toxins and cause toxicological renal effects at high levels, but the relevance of low-level environmental exposures in the general population is controversial. A total of 1,797 adults who participated in the KNHANES (a cross-sectional nationally representative survey in Korea) were examined, and 128 of them (7.1%) had chronic kidney disease (CKD). Our study assessed the association between Pb, Hg, Cd exposure, and CKD. Blood Pb and Cd levels were correlated with CKD in univariate logistic regression model. However, these environmental heavy metals were not associated with CKD after adjustment for age, sex, BMI, smoking, hyperlipidemia, hypertension, diabetes, and these metals in multivariate logistic regression models. We stratified the analysis according to hypertension or diabetes. In the adults with hypertension or diabetes, CKD had a significant association with elevated blood Cd after adjustment, but no association was present with blood Pb and Hg. The corresponding odds ratio [OR] of Cd for CKD were 1.52 (95% confidence interval [CI], 1.05-2.19, P=0.026) in adults with hypertension and 1.92 (95% CI, 1.14-3.25, P=0.014) in adults with diabetes. Environmental low level of Pb, Hg, Cd exposure in the general population was not associated with CKD. However, Cd exposure was associated with CKD, especially in adults with hypertension or diabetes. This finding suggests that environmental low Cd exposure may be a contributor to the risk of CKD in adults with hypertension or diabetes.
Graphical Abstract
doi:10.3346/jkms.2015.30.3.272
PMCID: PMC4330481  PMID: 25729249
Renal Insufficiency; Environmental Low Exposure; Lead; Mercury; Cadmium
6.  Identification of novel PKD1 and PKD2 mutations in Korean patients with autosomal dominant polycystic kidney disease 
BMC Medical Genetics  2014;15:129.
Background
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disorder. It is caused by mutations in the PKD1 and PKD2 genes, and manifests as progressive cyst growth and renal enlargement, resulting in renal failure. Although there have been a few studies on the frequency and spectrum of mutations in PKD1 and PKD2 in Korean patients with ADPKD, only exons 36–46, excluding the duplicated region, were analyzed, which makes it difficult to determine accurate mutation frequencies and mutation spectra.
Methods
We performed sequence analysis of 20 consecutive unrelated ADPKD patients using long-range polymerase chain reaction (PCR) to avoid pseudogene amplification, followed by exon-specific PCR and sequencing of the all exons of these two genes. Multiplex ligation-dependent probe amplification was performed in patients in whom pathogenic mutations in PKD1 or PKD2 were not identified by LR-PCR and direct sequencing to detect large genomic rearrangements.
Results
All patients met the diagnostic criteria of ADPKD, and pathogenic mutations were found in 18 patients (90.0%), comprising 15 mutations in PKD1 and three in PKD2. Among 10 novel mutations, eight mutations were found in the PKD1 gene while two mutations were found in the PKD2 gene. Eight of 14 PKD1 mutations (57.1%) were located in the duplicated region.
Conclusions
This study expands the spectra of mutations in the PKD1 and PKD2 genes and shows that the mutation frequencies of these genes in Korean ADPKD patients are similar to those reported in other ethnicities. Sequence analysis, including analysis of the duplicated region, is essential for molecular diagnosis of ADPKD.
doi:10.1186/s12881-014-0129-y
PMCID: PMC4411869  PMID: 25491204
Autosomal dominant polycystic kidney disease; Korean; Mutation; PKD1; PKD2
7.  Human Cytomegalovirus (HCMV) US2 Protein Interacts with Human CD1d (hCD1d) and Down-Regulates Invariant NKT (iNKT) Cell Activity 
Molecules and Cells  2013;36(5):455-464.
To avoid host immune surveillance, human cytomegalovirus (HCMV) encoded endoplasmic reticulum (ER)-membrane glycoprotein US2, which interferes with antigen presenting mechanism of major histocompatibility complex (MHC) class Ia and class II molecules. However, not many attempts have been made to study the effect of HCMV US2 on the expression of MHC class Ib molecules. In this study, we examined the effect of HCMV US2 on the expression and function of human CD1d (hCD1d), which presents glycolipid antigens to invariant NKT (iNKT) cells. Our results clearly showed that the physiological interaction between ER lumenal domain of HCMV US2 and α3 domain of hCD1d was observed within ER. Compared with mature form of hCD1d, immature form of hCD1d is more susceptible to ubiquitin-dependent proteasomal degradation mediated by HCMV US2. Moreover, the ectopic expression of HCMV US2 leads to the down-modulation of iNKT cell activity without significant change of hCD1d expression. These results will advance our understanding of the function of HCMV US2 in immune evasive mechanisms against anti-viral immunity of iNKT cells.
doi:10.1007/s10059-013-0221-8
PMCID: PMC3887943  PMID: 24213674
antigen presentation; HCMV US2 protein; human CD1d; human cytomegalovirus; invariant NKT cell
8.  No expression of porcine endogenous retrovirus after pig to monkey xenotransplantation 
Laboratory Animal Research  2014;30(2):90-93.
This study was performed to investigate the expression of two porcine endogenous retrovirus (PERV) elements, PERV gag and full-length conserved PERV, in blood cells collected periodically from organ-recipient monkeys that underwent pig to non-human primate xenotransplantation. The heart and kidney-respectively acquired from α-1,3-galactosyltransferase knockout (GT-KO) pigs that survived for24 and 25 days-were xenografted into cynomolgus monkeys. The two PERV elements expressed in the xenografted GT-KO pig organs were not present in the blood cells of the recipient monkeys. In the present study, we deduced that PERVs are not transmitted during GT-KO pig to monkey xenotransplantation.
doi:10.5625/lar.2014.30.2.90
PMCID: PMC4079837  PMID: 24999364
PERV transmission; GT-KO pigs; cynomolgus monkey; xenotransplantation; blood cells
9.  KNOW-CKD (KoreaN cohort study for Outcome in patients With Chronic Kidney Disease): design and methods 
BMC Nephrology  2014;15:80.
Background
The progression and complications of chronic kidney disease should differ depending on the cause (C), glomerular filtration rate category (G), and albuminuria (A). The KNOW-CKD (KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease), which is a prospective cohort study, enrolls subjects with chronic kidney disease stages 1 to 5 (predialysis).
Methods/Design
Nine nephrology centers in major university hospitals throughout Korea will enroll approximately 2,450 adults with chronic kidney disease over a 5-year period from 2011 to 2015. The participating individuals will be monitored for approximately 10 years until death or until end-stage renal disease occurs. The subjects will be classified into subgroups based on the following specific causes of chronic kidney disease: glomerulonephritis, diabetic nephropathy, hypertensive nephropathy, polycystic kidney disease, and others. The eligible subjects will be evaluated at baseline for socio-demographic information, detailed personal/family history, office BP, quality of life, and health behaviors. After enrollment in the study, thorough assessments, including laboratory tests, cardiac evaluation and radiologic imaging, will be performed according to the standardized protocol. The biospecimen samples will be collected regularly. A renal event is defined by >50% decrease in estimated GFR (eGFR) from the baseline values, doubling of serum creatinine, or end-stage renal disease. The primary composite outcome consists of renal events, cardiovascular events, and death. As of September 2013, 1,470 adult chronic kidney disease subjects were enrolled in the study, including 543 subjects with glomerulonephritis, 317 with diabetic nephropathy, 294 with hypertensive nephropathy and 249 with polycystic kidney disease.
Discussion
As the first large-scale chronic kidney disease cohort study to be established and maintained longitudinally for up to 10 years, the KNOW-CKD will help to clarify the natural course, complication profiles, and risk factors of Asian populations with chronic kidney disease.
Trial registration
No. NCT01630486 at http://www.clinicaltrials.gov.
doi:10.1186/1471-2369-15-80
PMCID: PMC4050398  PMID: 24884708
KNOW-CKD; Chronic kidney disease; Cohort; Etiology; Progression; Complication; Natural course
10.  KNOW-KT (KoreaN cohort study for outcome in patients with kidney transplantation: a 9-year longitudinal cohort study): study rationale and methodology 
BMC Nephrology  2014;15:77.
Background
Asian patients undergoing kidney transplantation (KT) generally have better renal allograft survival and a lower burden of cardiovascular disease than those of other racial groups. The KNOW-KT aims to explore allograft survival rate, cardiovascular events, and metabolic profiles and to elucidate the risk factors in Korean KT patients.
Methods
KNOW-KT is a multicenter, observational cohort study encompassing 8 transplant centers in the Republic of Korea. KNOW-KT will enroll 1,000 KT recipients between 2012 and 2015 and follow them up to 9 years. At the time of KT and at pre-specified intervals, clinical information, laboratory test results, and functional and imaging studies on cardiovascular disease and metabolic complications will be recorded. Comorbid status will be assessed by the age-adjusted Charlson co-morbidity index. Medication adherence and information on quality of life (QoL) will be monitored periodically. The QoL will be assessed by the Kidney Disease Quality of Life Short Form. Donors will include both living donors and deceased donors whose status will be assessed by the Kidney Donor Risk Index. Primary endpoints include graft loss and patient mortality. Secondary endpoints include renal functional deterioration (a decrease in eGFR to <30 mL/min/1.73 m2), acute rejection, cardiovascular event, albuminuria, new-onset diabetes after transplant, and QoL. Data on other adverse outcomes including episodes of infection, malignancy, recurrence of original renal disease, fracture, and hospitalization will also be collected. A bio-bank has been established for the acquisition of DNA, RNA, and protein from serum and urine samples of recipients at regular intervals. Bio-samples from donors will also be collected at the time of KT. KNOW-KT was registered in an international clinical trial registry (NCT02042963 at http://www.clinicaltrials.gov) on January 20th, 2014.
Conclusion
The KNOW-KT, the first large-scale cohort study in Asian KT patients, is expected to represent the Asian KT population and provide information on their natural course, complications, and risk factors for complications.
doi:10.1186/1471-2369-15-77
PMCID: PMC4022441  PMID: 24884405
Cohort study; Complication; Kidney transplantation; KNOW-KT; Risk factor
11.  Hyperuricemia and deterioration of renal function in autosomal dominant polycystic kidney disease 
BMC Nephrology  2014;15:63.
Background
The role of hyperuricemia in disease progression of autosomal dominant polycystic kidney disease (ADPKD) has not been defined well. We investigated the association of serum uric acid (sUA) with renal function and the effect of hypouricemic treatment on the rate of renal function decline.
Methods
This is a single-center, retrospective, observational cohort study. A total of 365 patients with ADPKD who had estimated glomerular filtration rate (eGFR) ≥ 15 mL/min/1.73 m2 and who were followed up for > 1 year were included in our analysis. Hyperuricemia was defined by a sUA level of ≥ 7.0 mg/dL in male and ≥ 6.0 mg/dL in female or when hypouricemic medications were prescribed.
Results
Hyperuricemia was associated with reduced initial eGFR, independent of age, sex, hypertension, albuminuria, and total kidney volume. During a median follow-up period of over 6 years, patients with hyperuricemia showed a faster annual decline in eGFR (−6.3% per year vs. −0.9% per year, p = 0.008). However, after adjusting for age, sex, hypertension and initial eGFR, sUA was no longer associated with either annual eGFR decline or the development of ESRD. Among 53 patients who received hypouricemic treatment, the annual eGFR decline appeared to be attenuated after hypouricemic treatment (pretreatment vs. posttreatment: −5.3 ± 8. 2 vs. 0.2 ± 6.2 mL/min/1.73 m2 per year, p = 0.001 by Wilcoxon signed-rank test).
Conclusions
Although hyperuricemia was associated with reduced eGFR, it was not an independent factor for renal progression in ADPKD. However, the correction of hyperuricemia may attenuate renal function decline in some patients with mild renal insufficiency.
doi:10.1186/1471-2369-15-63
PMCID: PMC4021172  PMID: 24739095
Glomerular filtration rate; Hyperuricemia; Polycystic kidney; Autosomal dominant; Uric acid
12.  Impact of Combined Acute Rejection on BK Virus-Associated Nephropathy in Kidney Transplantation 
Journal of Korean Medical Science  2013;28(12):1711-1715.
BK virus-associated nephropathy (BKVAN) is one of the major causes of allograft dysfunction in kidney transplant (KT) patients. We compared BKVAN combined with acute rejection (BKVAN/AR) with BKVAN alone in KT patients. We retrospectively analyzed biopsy-proven BKVAN in KT patients from 2000 to 2011 at Seoul National University Hospital. Among 414 biopsies from 951 patients, biopsy-proven BKVAN was found in 14 patients. Nine patients had BKVAN alone, while 5 patients had both BKVAN and acute cellular rejection. BKVAN in the BKVAN alone group was detected later than in BKVAN/AR group (21.77 vs 6.39 months after transplantation, P=0.03). Serum creatinine at diagnosis was similar (2.09 vs 2.00 mg/dL). Histological grade was more advanced in the BKVAN/AR group (P=0.034). Serum load of BKV, dose of immunosuppressants, and tacrolimus level showed a higher tendency in the BKVAN alone group; however it was not statistically significant. After anti-rejection therapy, immunosuppression was reduced in the BKVAN/AR group. Renal functional deterioration over 1 yr after BKVAN diagnosis was similar between the two groups (P=0.665). These findings suggest that the prognosis of BKVAN/AR after anti-rejection therapy followed by anti-BKV therapy might be similar to that of BKVAN alone after anti-BKV therapy.
doi:10.3346/jkms.2013.28.12.1711
PMCID: PMC3857364  PMID: 24339698
Acute Rejection; BK Virus; Kidney Diseases; Kidney Transplantation
13.  Expression Analysis of Combinatorial Genes Using a Bi-Cistronic T2A Expression System in Porcine Fibroblasts 
PLoS ONE  2013;8(7):e70486.
In pig-to-primate xenotransplantation, multiple transgenic pigs are required to overcome a series of transplant rejections. The generation of multiple transgenic pigs either by breeding or the introduction of several mono-cistronic vectors has been hampered by the differential expression patterns of the target genes. To achieve simultaneous expression of multiple genes, a poly-cistronic expression system using the 2A peptide derived from the Thosea asigna virus (T2A) can be considered an alternative choice. Before applying T2A expression system to pig generation, the expression patterns of multiple genes in this system should be precisely evaluated. In this study, we constructed several bi-cistronic T2A expression vectors, which combine target genes that are frequently used in the xenotransplantation field, and introduced them into porcine fibroblasts. The proteins targeted to the same or different subcellular regions were efficiently expressed without affecting the localization or expression levels of the other protein. However, when a gene with low expression efficiency was inserted into the upstream region of the T2A sequences, the expression level of the downstream gene was significantly decreased compared with the expression efficiency without the insertion. A small interfering RNA targeting one gene in this system resulted in the significant downregulation of both the target gene and the other gene, indicating that multiple genes combined into a T2A expression vector can be considered as a single gene in terms of transcription and translation. In summary, the efficient expression of a downstream gene can be achieved if the expression of the upstream gene is efficient.
doi:10.1371/journal.pone.0070486
PMCID: PMC3726604  PMID: 23922997
14.  Successfully Treated Escherichia coli-Induced Emphysematous Cyst Infection with Combination of Intravenous Antibiotics and Intracystic Antibiotics Irrigation in a Patient with Autosomal Dominant Polycystic Kidney Disease 
Journal of Korean Medical Science  2013;28(6):955-958.
A 62-yr-old woman with an autosomal dominant polycystic kidney disease (ADPKD) was admitted to our hospital for further evaluation of intermittent fever, nausea and left flank discomfort. The computed tomography (CT) scan revealed a gas-forming, infectious cyst of approximately 8.1 cm in size in left kidney lower pole. Escherichia coli was identified from the cyst fluid culture examination. Her symptoms improved only after the concomitant use of intravenous ciprofloxacin and an intracystic irrigation of ciprofloxacin through a percutaneous cystostomy drainage. Our case presents the successfully treated emphysematous cyst infection with combination of intravenous antibiotics and intracystic antibiotic therapy instead of surgical management.
doi:10.3346/jkms.2013.28.6.955
PMCID: PMC3678017  PMID: 23772165
Autosomal Dominant Polycystic Kidney Disease; Escherichia coli; Emphysematous
15.  Cinacalcet lowering of serum fibroblast growth factor-23 concentration may be independent from serum Ca, P, PTH and dose of active vitamin D in peritoneal dialysis patients: a randomized controlled study 
BMC Nephrology  2013;14:112.
Background
Elevated serum level of fibroblast growth factor-23 (FGF23) is associated with adverse outcomes in dialyzed patients.
Objectives
The CUPID study compared the efficacy of a cinacalcet-based regimen with conventional care (vitamin D and P binders) for achieving the stringent NKF-K/DOQI targets for peritoneal dialysis (PD) patients. Additionally, we analyzed change in FGF23 levels between two treatments to explore the cinacalcet effect in lowering FGF23.
Design
Multicenter, open-labeled, randomized controlled study.
Setting
Seven university-affiliated hospitals in Korea.
Participants
Overall, 66 peritoneal dialysis patients were enrolled.
Intervention
Sixty six patients were randomly assigned to treatment with either cinacalcet + oral vitamin D (cinacalcet group, n = 33) or oral vitamin D alone (control group, n = 33) to achieve K/DOQI targets. CUPID included a 4-week screening for vitamin D washout, a 12-week dose-titration, and a 4-week assessment phases. We calculated mean values of iPTH, Ca, P, Ca x P, during assessment phase and final FGF23 to assess the outcome.
Main outcome measures
Achievement of >30% reduction of iPTH from baseline (primary) and FGF23 reduction (secondary).
Results
72.7% (n = 24) of the cinacalcet group and 93.9% (n = 31) of the control group completed the study. Cinacalcet group received 30.2 ± 18.0 mg/day of cinacalcet and 0.13 ± 0.32 μg/d oral vitamin D (P < 0.001 vs. control with 0.27 ± 0.18 μg/d vitamin D). The proportion of patients who reached the primary endpoint was not statistically different (48.5% vs. 51.5%, cinacalcet vs. control, P = 1.000). After treatment, cinacalcet group experienced a significant reduction in FGF23 levels (median value from 3,960 to 2,325 RU/ml, P = 0.002), while an insignificant change was shown for control group (from 2,085 to 2,415 RU/ml). The percent change of FGF23 after treatment was also significantly different between the two groups (− 42.54% vs. 15.83%, P = 0.008). After adjustment, cinacalcet treatment was independently associated with the serum FGF23 reduction.
Conclusion
Cinacalcet treatment was independently associated with the reduction of FGF23 in our PD patients.
Trial registration
Controlled trials NCT01101113
doi:10.1186/1471-2369-14-112
PMCID: PMC3669111  PMID: 23705925
Cinacalcet; Fibroblast growth factor 23; Peritoneal dialysis
16.  CD70–CD27 ligation between neural stem cells and CD4+ T cells induces Fas–FasL-mediated T-cell death 
Introduction
Neural stem cells (NSCs) are among the most promising candidates for cell replacement therapy in neuronal injury and neurodegenerative diseases. One of the remaining obstacles for NSC therapy is to overcome the alloimmune response on NSCs by the host.
Methods
To investigate the mechanisms of immune modulatory function derived from the interaction of human NSCs with allogeneic T cells, we examined the immune regulatory effects of human NSCs on allogeneic T cells in vitro.
Results
Significantly, NSCs induced apoptosis of allogeneic T cells, in particular CD4+ T cells. Interaction of CD70 on NSCs and CD27 on CD4+ T cells mediated apoptosis of T cells. Thus, blocking CD70–CD27 interaction prevented NSC-mediated death of CD4+ T cells.
Conclusions
We present a rational explanation of NSC-induced immune escape in two consecutive stages. First, CD70 constitutively expressed on NSCs engaged CD27 on CD4+ T cells, which induced Fas ligand expression on CD4+ T cells. Second, CD4+ T-cell apoptosis was followed by Fas–Fas ligand interaction in the CD4+ T cells.
doi:10.1186/scrt206
PMCID: PMC3706991  PMID: 23692980
Neural stem cells; Co-stimulatory molecules; Immune escape mechanism
17.  Chronic asymptomatic pyuria precedes overt urinary tract infection and deterioration of renal function in autosomal dominant polycystic kidney disease 
BMC Nephrology  2013;14:1.
Background
Urinary tract infection (UTI) occurs in 30%-50% of individuals with autosomal dominant polycystic kidney disease (ADPKD). However, the clinical relevance of asymptomatic pyuria in ADPKD patients remains unknown.
Methods
We retrospectively reviewed medical records of 256 ADPKD patients who registered to the ADPKD clinic at Seoul National University Hospital from Aug 1999 to Aug 2010. We defined the asymptomatic pyuria as more than 5-9 white blood cells in high-power field with no related symptoms or signs of overt UTI. Patients were categorized into 2 groups depending on its duration and frequency: Group A included non-pyuria and transient pyuria patients; Group B included recurrent and persistent pyuria patients. The association between asymptomatic pyuria and both the development of overt UTI and the deterioration of renal function were examined.
Results
With a mean follow-up duration of 65.3 months, 176 (68.8%) out of 256 patients experienced 681 episodes of asymptomatic pyuria and 50 episodes of UTI. The annual incidence of asymptomatic pyuria was 0.492 episodes/patient/year. The patients in group B showed female predominance (58.5% vs. 42.0%, P=0.01) and experienced an upper UTI more frequently (hazard ratio: 4.612, 95% confidence interval: 1.735-12.258; P=0.002, adjusted for gender and hypertension). The annual change in estimated glomerular filtration rate (ΔeGFR) was significantly larger in magnitude in group B than in group A (-2.7±4.56 vs. -1.17±5.8, respectively; P=0.01). Age and Group B found to be the independent variables for ΔeGFR and developing end-stage renal disease (16.0% vs. 4.3%, respectively; P=0.001).
Conclusions
Chronic asymptomatic pyuria may increase the risk of developing overt UTI and may contribute to declining renal function in ADPKD.
doi:10.1186/1471-2369-14-1
PMCID: PMC3545884  PMID: 23295127
Polycystic kidney disease; Chronic renal failure; Glomerular filtration rate; Pyuria; Urinary tract infection
18.  Chronic allograft injury by subclinical borderline change: evidence from serial protocol biopsies in kidney transplantation 
Purpose
This study investigated the impact of subclinical borderline changes on the development of chronic allograft injury in patients using a modern immunosuppression protocol.
Methods
Seventy 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.
Results
The 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.
Conclusion
Subclinical borderline changes can be a risk factor for chronic allograft injury and should be considered for antirejection therapy.
doi:10.4174/jkss.2012.83.6.343
PMCID: PMC3514476  PMID: 23230552
Borderline change; Chronic allograft injury; Kidney transplantation; Protocol kidney biopsy; Steroid pulse therapy
19.  Generation and Characterization of Human Heme Oxygenase-1 Transgenic Pigs 
PLoS ONE  2012;7(10):e46646.
Xenotransplantation using transgenic pigs as an organ source is a promising strategy to overcome shortage of human organ for transplantation. Various genetic modifications have been tried to ameliorate xenograft rejection. In the present study we assessed effect of transgenic expression of human heme oxygenase-1 (hHO-1), an inducible protein capable of cytoprotection by scavenging reactive oxygen species and preventing apoptosis caused by cellular stress during inflammatory processes, in neonatal porcine islet-like cluster cells (NPCCs). Transduction of NPCCs with adenovirus containing hHO-1 gene significantly reduced apoptosis compared with the GFP-expressing adenovirus control after treatment with either hydrogen peroxide or hTNF-α and cycloheximide. These protective effects were diminished by co-treatment of hHO-1 antagonist, Zinc protoporphyrin IX. We also generated transgenic pigs expressing hHO-1 and analyzed expression and function of the transgene. Human HO-1 was expressed in most tissues, including the heart, kidney, lung, pancreas, spleen and skin, however, expression levels and patterns of the hHO-1 gene are not consistent in each organ. We isolate fibroblast from transgenic pigs to analyze protective effect of the hHO-1. As expected, fibroblasts derived from the hHO-1 transgenic pigs were significantly resistant to both hydrogen peroxide damage and hTNF-α and cycloheximide-mediated apoptosis when compared with wild-type fibroblasts. Furthermore, induction of RANTES in response to hTNF-α or LPS was significantly decreased in fibroblasts obtained from the hHO-1 transgenic pigs. These findings suggest that transgenic expression of hHO-1 can protect xenografts when exposed to oxidative stresses, especially from ischemia/reperfusion injury, and/or acute rejection mediated by cytokines. Accordingly, hHO-1 could be an important candidate molecule in a multi-transgenic pig strategy for xenotransplantation.
doi:10.1371/journal.pone.0046646
PMCID: PMC3465346  PMID: 23071605
20.  Change in Body Compositions of Asian Recipients after Kidney Transplantation 
Journal of Korean Medical Science  2012;27(10):1182-1187.
Kidney transplantation and accompanying medical conditions may result in changes in body composition. Such changes have been evaluated in Caucasian recipients, but not in Asian recipients. Herein, we conducted a study on Asian recipients because Asians have a different body composition from Caucasians. A total of 50 Asian recipients was enrolled as a prospective cohort. Using bioelectrical impedance analysis, body composition (muscle and fat mass) was assessed after 2 weeks (baseline), and at 1, 3, 6, 9, and 12 months following kidney transplantation. To find predictors related to changes, the data were analyzed by multivariate analysis using forward selection. All of the patients had good graft function during the study period. Patients gained approximately 3 kg within 1 yr of kidney transplantation. The proportion of muscle mass significantly decreased (Ptrend = 0.001) and the proportion of fat mass significantly increased over time (Ptrend = 0.002). The multivariate results revealed that male recipients, deceased donor type, and low protein intake were associated with an increase in fat mass and a decrease in muscle mass. The results from this study may help to investigate differences in body composition changes between races, as well as the factors related to these changes.
doi:10.3346/jkms.2012.27.10.1182
PMCID: PMC3468754  PMID: 23091315
Asian; Body Composition; Fat; Kidney Transplantation; Muscle
21.  Urinary N-acetyl-β-D glucosaminidase as a surrogate marker for renal function in autosomal dominant polycystic kidney disease: 1 year prospective cohort study 
BMC Nephrology  2012;13:93.
Background
Renal failure is one of the most serious complications associated with autosomal dominant polycystic kidney disease (ADPKD). To date, early markers have failed to predict renal function deterioration at the early stages. This 1-year prospective study evaluated N-acetyl-β-D-glucosaminidase (NAG) as a new surrogate marker for renal function in ADPKD.
Methods
A total of 270 patients were enrolled in the study, and we measured urinary NAG, β2-microglobulin, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1) prospectively for 1 year to compare their predictive values for renal function.
Results
Baseline urinary NAG/Cr was negatively correlated with estimated glomerular filtration rate (GFR) (r2 = 0.153, P < 0.001) and positively correlated with total kidney volume (TKV) (r2 = 0.113, P < 0.001). Among other biomarkers, urinary NAG/Cr better discriminated patients with decreased renal function from those with conserved renal function, showing the largest area under the curve (AUC 0.794). Immunohistochemical study revealed strong staining along the cyst-lining epithelial cells as well as the nearby compressed tubular epithelial cells. However, both single and repeated measurements of urinary NAG/Cr failed to predict renal function decline in 1 year.
Conclusions
Urinary NAG/Cr may be a useful surrogate marker for renal function in ADPKD patients.
doi:10.1186/1471-2369-13-93
PMCID: PMC3465238  PMID: 22935351
Autosomal dominant polycystic kidney disease; Biomarkers; Renal function
22.  Clinical Relevance of Pretransplant HLA Class II Donor-specific Antibodies in Renal Transplantation Patients with Negative T-cell Cytotoxicity Crossmatches 
Annals of Laboratory Medicine  2012;32(2):139-144.
Background
We evaluated the clinical relevance of pretransplant donor-specific HLA antibodies (DSA) in renal transplantation patients who had negative T-cell cytotoxicity crossmatches.
Methods
From 328 consecutive renal transplant recipients, we selected 28 patients who had positive pretransplant (historical or at the time of transplantation) flow cytometry crossmatches, but negative T-cell cytotoxicity crossmatches at the time of transplantation. The presence of DSA and its level at the time of transplantation were retrospectively tested using Luminex single antigen assays.
Results
DSA was present in 16 (57.1%) of 28 patients. Biopsy-proven acute rejection (9 patients) occurred more frequently in patients with DSA than in those without DSA (56.3% vs. 0.0%; P=0.003). The positivity rate of class II DSA was significantly higher in patients with antibody-mediated rejection (AMR) than in those without AMR (100% vs. 21.7%; P=0.003). However, the positivity rate of class I DSA was not different between the two groups (40% vs. 40.9%). Among patients with class II DSA, those with AMR tended to have higher antibody levels (median fluorescence intensity, MFI) than those without AMR (16,359 vs. 5,910; P=0.056). A cut-off MFI value of 4,487 for class II DSA predicted the occurrence of AMR with good sensitivity and specificity (100% and 87.0%).
Conclusions
In patients with negative T-cell cytotoxicity crossmatches, the presence of class II DSA and its level at the time of transplantation were associated with the occurrence of AMR. Pretransplant DSA measurement with Luminex single antigen assay would be useful in renal transplantation.
doi:10.3343/alm.2012.32.2.139
PMCID: PMC3289779  PMID: 22389881
Donor-specific HLA antibodies; Renal transplantation; Antibody-mediated rejection
23.  Outcome of Early Initiation of Peritoneal Dialysis in Patients with End-Stage Renal Failure 
Journal of Korean Medical Science  2012;27(2):170-176.
Recent studies reported that early initiation of hemodialysis may increase mortality. However, studies that assessed the influence of early initiation of peritoneal dialysis (PD) yielded controversial results. In the present study, we evaluated the prognosis of early initiation of PD on the various outcomes of end stage renal failure patients by using propensity-score matching methods. Incident PD patients (n = 491) who started PD at SNU Hospital were enrolled. The patients were divided into 'early starters (n = 244)' and 'late starters (n = 247)' on the basis of the estimated glomerular filtration rate (eGFR) at the start of dialysis. The calculated propensity-score was used for one-to-one matching. After propensity-score-based matching (n = 136, for each group), no significant differences were observed in terms of all-cause mortality (P = 0.17), technique failure (P = 0.62), cardiovascular event (P = 0.96) and composite event (P = 0.86) between the early and late starters. Stratification analysis in the propensity-score quartiles (n = 491) exhibited no trend toward better or poorer survival in terms of all-cause mortality. In conclusion, early commencement of PD does not reduce the mortality risk and other outcomes. Although the recent guidelines suggest that initiation of dialysis at higher eGFR, physicians should not determine the time to initiate PD therapy simply rely on the eGFR alone.
doi:10.3346/jkms.2012.27.2.170
PMCID: PMC3271290  PMID: 22323864
Peritoneal Dialysis; End Stage Renal Failure; Dialysis Initiation; Propensity Score Match; Outcome; Survival
24.  Functional improvement of porcine neonatal pancreatic cell clusters via conformal encapsulation using an air-driven encapsulator 
Transplantation of islet cells into diabetic patients is a promising therapy, provided that the islet cells are able to evade host immune rejection. With improved islet viability, this strategy may effectively reverse diabetes. We applied 2% calcium alginate to generate small and large capsules to encapsulate porcine neonatal pancreatic cell clusters (NPCCs) using an air-driven encapsulator. After encapsulation, the viability was assessed at 1, 4, 7, 14 and 28 days and secretion of functional insulin in response to glucose stimulation were tested at days 14 and 28. Selective permeability of the small alginate capsules was confirmed using various sizes of isothiocyanate-labeled dextran (FITC-dextran). Encapsulation of NPCCs was performed without islet protrusion in the small and large capsules. The viability of NPCCs in all experimental groups was greater than 90% at day 1 and then gradually decreased after day 7. The NPCCs encapsulated in large capsules showed significantly lower viability (79.50 ± 2.88%) than that of naïve NPCCs and NPCCs in small capsule (86.83 ± 2.32%, 87.67 ± 2.07%, respectively) at day 7. The viability of naïve NPCCs decreased rapidly at day 14 (75.67 ± 1.75%), whereas the NPCCs encapsulated in small capsules maintained (82.0 ± 2.19%). After 14 and 28 days NPCCs' function in small capsules (2.67 ± 0.09 and 2.13 ± 0.09) was conserved better compared to that of naïve NPCCs (2.04 ± 0.25 and 1.53 ± 0.32, respectively) and NPCCs in large capsules (2.04 ± 0.34 and 1.13 ± 0.10, respectively), as assessed by a stimulation index. The small capsules also demonstrated selective permeability. With this encapsulation technique, small capsules improved the viability and insulin secretion of NPCCs without islet protrusion.
doi:10.3858/emm.2012.44.1.001
PMCID: PMC3277894  PMID: 22020445
alginic acid; diabetes mellitus type 1; insulin-secreting cells; islets of Langerhans transplantation; tissue therapy
25.  Lower Residual Renal Function is a Risk Factor for Depression and Impaired Health-Related Quality of Life in Korean Peritoneal Dialysis Patients 
We retrospectively evaluated demographic and biochemical parameters associated with depression and health-related quality of life (HRQOL) in maintenance peritoneal dialysis (PD) patients. This study included 105 patients maintaining PD at Seoul National University Hospital. Data were collected from electronic medical record. Korean Beck's Depression Inventory and Korean version of Kidney Disease Quality of Life short form, version 1.3 were used to evaluate depression and HRQOL, respectively. Moderate to severe depression was found in 24.8% of patients. Patients with lower normalized protein equivalent of nitrogen appearance (nPNA) (< 1.2 g/kg/day), lower weekly renal Kt/Vurea (< 0.2), and lower serum albumin level (≤ 4.0 g/dL) were associated with depression (P < 0.05). Among them, lower weekly renal Kt/Vurea was the only independent risk factor associated with depression (OR = 3.1, P = 0.007). Depressed patients showed significantly lower scores in every dimension of HRQOL (P < 0.001). Lower weekly renal Kt/Vurea (β = 0.24, P = 0.005) and lower nPNA (β = 0.15, P = 0.03) were the independent risk factors associated with lower kidney dialysis component summary, whereas lower plasma hemoglobin level was the consistent risk factor for lower physical component summary (β = 0.22, P = 0.03) and mental component summary (β = 0.22, P = 0.01). Depression is a prevalent psychological problem in PD population. Residual renal function is the most important factor associated with depression and impaired HRQOL in PD patients.
doi:10.3346/jkms.2012.27.1.64
PMCID: PMC3247777  PMID: 22219616
Peritoneal Dialysis; Depression; Health-Related Quality of Life; Residual Renal Function; Beck's Depression Inventory; KDQOL-SF

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