Chan-Duck Kim

Proteomic analysis of urinary exosomes from patients of early IgA nephropathy and thin basement membrane nephropathy

To identify biomarker candidates associated with early IgA nephropathy (IgAN) and thin basement membrane nephropathy (TBMN), the most common causes presenting isolated hematuria in childhood, a proteomic approach of urinary exosomes from early IgAN and TBMN patients was introduced. The proteomic results from the patients were compared with a normal group to understand the pathophysiological processes associated with these diseases at the protein level. The urinary exosomes, which reflect pathophysiological processes, collected from three groups of young adults (early IgAN, TBMN, and normal) were trypsin‐digested using a gel‐assisted protocol, and quantified by label‐free LC‐MS/MS, using an MSE mode. A total of 1877 urinary exosome proteins, including cytoplasmic, membrane, and vesicle trafficking proteins, were identified. Among the differentially expressed proteins, four proteins (aminopeptidase N, vasorin precursor, α‐1‐antitrypsin, and ceruloplasmin) were selected as biomarker candidates to differentiate early IgAN from TBMN. We confirmed the protein levels of the four biomarker candidates by semi‐quantitative immunoblot analysis in urinary exosomes independently prepared from other patients, including older adult groups. Further clinical studies are needed to investigate the diagnostic and prognostic value of these urinary markers for early IgAN and TBMN. Taken together, this study showed the possibility of identifying biomarker candidates for human urinary diseases using urinary exosomes and might help to understand the pathophysiology of early IgAN and TBMN at the protein level.

Effects of neutral pH and low-glucose degradation product-containing peritoneal dialysis fluid on systemic markers of inflammation and endothelial dysfunction: a randomized controlled 1-year follow-up study

BACKGROUNDnThe local peritoneal effects of low-glucose degradation product (GDP)-containing peritoneal dialysis fluid (PDF) have been extensively described. However, the systemic effects of prolonged prescription of these solutions are unknown. This study aimed to evaluate the effects of neutral pH and low-GDP PDF on systemic inflammation and endothelial dysfunction markers in peritoneal dialysis (PD) patients.nnnMETHODSnThis is a multicenter, open labeled, randomized controlled trial including one hundred fifty-two patients initiating continuous ambulatory peritoneal dialysis for end-stage renal disease from seven centers in Korea. Participants were randomly allocated to conventional PDF (Stay safe®; Fresenius Medical Care, Bad Homburg, Germany) or low-GDP PDF (Balance®; Fresenius Medical Care) and were followed for 1 year. Primary outcome variable was the inflammation and endothelial dysfunction index (IEDI), a composite score derived from serum levels of soluble intercellular adhesion molecule (sICAM)-1, soluble vascular cellular adhesion molecule (sVCAM)-1 and high-sensitivity C-reactive protein (hs-CRP). sICAM-1, sVCAM-1, residual renal function (RRF), peritoneal membrane transport characteristics, ultrafiltration volume and nutritional parameters were measured as secondary outcome variables.nnnRESULTSnOf 152 patients randomized, 146 (low-GDP: conventional PDF, 79:67) patients entered the trial (46% male, 53% with diabetes mellitus). At 12-month follow-up, the low-GDP group had significantly lower levels of IEDI, sICAM-1 and sVCAM-1 compared to the conventional group; hs-CRP was not different between groups. Peritoneal transport characteristics, RRF, nutritional parameters, incidence of peritonitis and death-censored technique survival were not different between groups.nnnCONCLUSIONnNeutral pH and low-GDP PDF likely produce fewer changes in markers of endothelial dysfunction compared to conventional PDF in incident PD patients.

The clinicopathological relevance of pretransplant anti-angiotensin II type 1 receptor antibodies in renal transplantation

BackgroundnAnti-angiotensin II type 1 receptor antibodies (AT1R-Abs) have been suggested as a risk factor for graft failure and acute rejection (AR). However, the prevalence and clinical significance of pretransplant AT1R-Abs have seldom been evaluated in Asia.nnnMethodsnIn this multicenter, observational cohort study, we tested the AT1R-Abs in pretransplant serum samples obtained from 166 kidney transplant recipients. Statistical analysis was used to set a threshold AT1R-Abs level at 9.05 U/mL.nnnResultsnPretransplant AT1R-Abs were detected in 98/166 (59.0%) of the analyzed recipients. No graft loss or patient death was reported during the study period. AT1R-Abs (+) patients had a significantly higher incidence of biopsy-proven AR than AT1R-Abs (-) patients (27.6 versus 10.3%, P = 0.007). Recipients with pretransplant AT1R-Abs had a 3.2-fold higher risk of AR within a year of transplantation (P = 0.006). Five study subjects developed microcirculation inflammation (score ≥2). Four of them were presensitized to AT1R-Abs. In particular, three patients had a high titer of anti-AT1R-Abs (>22.7 U/mL).nnnConclusionsnPretransplant AT1R-Abs is an independent risk factor for AR, especially acute cellular rejection, and is possibly associated with the risk of antibody-mediated injury. Pretransplant assessment of AT1R-Abs may be useful for stratifying immunologic risks.

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.

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.

Health-Related Quality of Life of Kidney Transplantation Patients: Results from the KoreaN Cohort Study for Outcome in Patients With Kidney Transplantation (KNOW-KT) Study

BACKGROUNDnAs patient and graft survival rates have been improving after kidney transplantation, health-related quality of life (HR-QOL) has become an important indicator of effective treatment. This study aimed to evaluate changes in HR-QOL after kidney transplantation.nnnMATERIALS AND METHODSnThe KoreaN cohort study for Outcome in patients With Kidney Transplantation (KNOW-KT) is a multicenter, observational, 9-year, cohort study. The HR-QOL of patients in the KNOW-KT study was assessed before transplantation and 2 years after transplantation using the Kidney Disease Quality of Life Short Form (KDQOL-SF) including chronic kidney disease targeted area and the Medical Outcome Study 36-item Short Form Health Survey (SF-36). Multivariate linear regression was used to identify significant factors associated with follow-up QOL scores.nnnRESULTSnA total of 175 patients from 8 centers were analyzed. All QOL scores including the total QOL score, chronic kidney disease targeted score, and SF-36xa0at the 2-year follow-up were significantly increased compared to baseline values. Both physical and mental scale scores were improved after transplantation.nnnCONCLUSIONnThe QOL scores for both the mental and physical scales were improved at 2 years after kidney transplantation. High glomerular filtration rate at 2 years, high baseline QOL score, and low body mass index were associated with good follow-up QOL scores. Kidney transplantation for an Asian population with end-stage renal disease can result in better QOL as well as better patient and graft survival.

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.