Dong Chan Jin

Expression of apoptosis-related genes in chronic cyclosporine nephrotoxicity in mice

To define the mechanism of cyclosporine (CsA)‐induced apoptosis, we investigated the expression of apoptosis‐related genes in experimental chronic CsA nephrotoxicity. Mice on a low‐salt (0.01%) diet were given vehicle (VH, olive oil, 1 mg/kg/day), or CsA (30 mg/kg/day), and sacrificed at 1 and 4 weeks. Apoptosis was detected with deoxynucleotidyl transferase‐mediated dUTP nick end‐labeling (TUNEL) stain, and the expressions of apoptosis‐related genes were evaluated by reverse transcription‐polymerase chain reaction, immunoblot or immunohistochemistry. The activity of caspase 1 and 3 was also evaluated. The CsA group showed increases in apoptotic cells compared with the VH group (54 ± 41 vs. 3 ± 3, p < 0.05), and the number of apoptotic cells correlated well with interstitial fibrosis scores (r = 0.83, p < 0.01). The CsA group showed a significant increase in Fas‐ligand mRNA (0.20 vs. 0.02 amol/μg total RNA, p < 0.05) and Fas protein expression (146% vs. 95%, p < 0.05), compared with the VH group. The CsA group showed significant increases in ICE mRNA (0.21 vs. 0.03 amol/μg total RNA at 4 weeks, p < 0.05) and CPP32 mRNA (0.18 vs. 0.03 amol/μg total RNA at 4 weeks, p < 0.05), compared with the VH group. The enzymatic activity of ICE (16.6 vs. 7.9 ρmol/μg/ h, p < 0.05) and CPP32 protease (15.6 vs. 2.7 ρmol/μg/ h, p < 0.05) proteases were increased in the CsA group, compared with the VH group. The ratio between bax and bcl‐2 protein increased significantly in the CsA group (5.3‐fold), compared with the VH group. Levels of p53 protein also increased in the CsA group. Immunohistochemical detection of Fas, Fas‐ligand, ICE and CPP32 revealed strong immunoreactivity in renal tubular cells in areas of structural injury. These findings suggest that local activation of the apoptosis‐related genes is associated with CsA‐induced apoptotic cell death.

Morphological Insights into the Origin of Glomerular Endothelial and Mesangial Cells and Their Precursors

Glomerular endothelial and mesangial cells may originate from the metanephric mesenchyme. We used the MAb Thy1.1, a mesangial cell marker in the adult rat kidney, and rat endothelial cell markers MAb RECA-1, MAb PECAM-1 (CD31), and MAb Flk-1 as potential markers to characterize the spatial and temporal distribution of mesangial and endothelial cell precursors during nephrogenesis in the rat. At early stages of glomerulogenesis, RECA-1- and Thy1.1-positive cells were detected in the metanephric blastema at 14 days post conception (dpc) embryos and 15 dpc, respectively, with Thy1.1 expression in cells surrounding the ureteric bud. At 17 and 18 dpc, both RECA-1- and Thy1.1-positive cells were found in the cleft of the S-shaped bodies and in the capillary loops of maturing glomeruli. Double staining for BrdU, a marker of proliferation, and for RECA-1 or BrdU and Thy1.1 also localize in the cleft of S-shaped bodies and in glomerular capillary loops at later stages of development. PDGFRβ co-localizes in cells expressing endothelial or mesangial markers. The data suggest that endothelial and mesangial cell precursors share common markers during the course of glomerulogenesis and that full differentiation of these cells occurs at late stages of glomerular maturation. Thy1.1- and RECA-1-positive cells may be derived from the metanephric blastemal cells at early stages of kidney development. A sub-population of these Thy1.1- or RECA-1-positive cells may be precursors that can migrate into the cleft of comma and S-shaped bodies and proliferate in situ to form glomerular capillary tufts.

Current status of dialytic therapy in Korea

SUMMARY:  The status of dialytic therapy in Korea at the end of 2001 was reported by the end‐stage renal disease (ESRD) registry committee of Korean Society of Nephrology, where data were collected through an internet on‐line registry program. The number of dialysis centres was 335 and the number of haemodialysis machines was 5529. The total number of patients with dialysis was 23 057 (haemodialysis 17 568, peritoneal dialysis 5489). Prevalence and incidence of dialysis patients were 477.5 and 96.4 patients per million population. The most common primary cause of end‐stage renal diseases was diabetic nephropathy (41.5%), hypertensive nephrosclerosis (15.4%), and chronic glomerulonephritis (13.6%). Eighty‐six percent of haemodialysis patients were on dialysis therapy three times a week, the mean urea reduction ratio was 66.7 ± 8.68% and mean Kt/V was 1.250 ± 0.292 in male patients; 1.526 ± 0.361 in female patients. The technical survival of haemodialysis in 5 years was 30.2% and peritoneal dialysis was 13.8%. The common complication of haemodialysis patients was hypertension (43.3%), gastrointestinal disease other than peptic ulcer (8.0%), congestive heart failure (7.6%), and of peritoneal dialysis patients were also hypertension (28.8%), congestive heart failure (5.0%), and peritonitis (4.8%). The most common causes of death were cardiac diseases (26.9%), vascular diseases, including cerebrovascular accidents (22.7%), and infection (17.8%).

Comparison of Clinical Outcome Between Twice-Weekly and Thrice-Weekly Hemodialysis in Patients With Residual Kidney Function

AbstractResidual kidney function (RKF) contributes to improved survival in hemodialysis (HD) patients. However, it is not clear whether RKF allows a comparable survival rate in patients undergoing twice-weekly HD compared with thrice-weekly HD.We enrolled 685 patients from a prospective multicenter observational cohort. RKF and HD adequacy was monitored regularly over 3-year follow-up. Patients with RKF were divided into groups undergoing twice-weekly HD (n = 113) or thrice-weekly HD (n = 137). Patients without RKF undergoing thrice-weekly HD (n = 435) were included as controls. Fluid balance and dialysis-associated characteristics were followed and clinical outcomes evaluated using all-cause mortality and cardiovascular events (CVE).In patients with RKF, baseline and follow-up RKF were significantly higher in patients undergoing twice-weekly HD than in those undergoing thrice-weekly HD. Total Kt/V urea (dialysis plus residual renal) in patients with RKF undergoing twice-weekly HD was greater than or equal to those in patients with or without RKF undergoing thrice-weekly HD. Compared with patients with RKF undergoing thrice-weekly HD, patients with RKF undergoing twice-weekly HD had no fluid excess, but their normalized protein catabolic rate became lower since 24-month follow up. In multivariable analyses, patients with RKF undergoing twice-weekly HD had a noninferior risk of mortality (hazard ratio [HR], 0.83; 95% confidence interval [95% CI], 0.34–2.01, P = 0.68) and of CVE (HR, 0.60; 95% CI, 0.28–1.29, P = 0.19) compared with patients without RKF undergoing thrice-weekly HD. However, this group showed an independent association with a greater risk of mortality compared with patients with RKF undergoing thrice-weekly HD (HR, 4.20; 95% CI, 1.02–17.32, P = 0.04).In conclusion, patients with RKF undergoing twice-weekly HD had an increased risk of mortality compared with those undergoing thrice-weekly HD. Decisions about twice-weekly HD should consider not only RKF, but also other risk factors such as normalized protein catabolic rate.

Effects of pretransplant plasmapheresis and rituximab on recurrence of focal segmental glomerulosclerosis in adult renal transplant recipients

Background/Aims Recurrent focal segmental glomerulosclerosis (FSGS) following renal transplantation is relatively common. However, the risk factors and optimal pretransplant treatment preventing recurrence of FSGS remain controversial. Methods We retrospectively reviewed 27 adult renal transplant recipients with FSGS over a period of 10 years. We first compared possible risk factors for FSGS recurrence between the recurrence and nonrecurrence groups. Then we evaluated the effect of pretransplant plasmapheresis (PP; n = 4) and PP with rituximab (PP + RTX; n = 5) on recurrence of FSGS after transplantation compared to control patients that were not treated with these modalities. Results There were seven recurrences in 27 patients (25.9%), but there were no significant differences in possible risk factors for FSGS recurrence between the two groups. Recurrence rates between patients with pretransplant PP or PP + RTX and control patients were not significantly different (22.2% vs. 27.7%, p > 0.05). There was also no significant difference in recurrence between the pretransplant PP and PP + RTX groups (25% vs. 20%, p > 0.05). Conclusions Pretransplant PP or PP + RTX do not significantly decrease the recurrence of FSGS in adult renal transplant candidates.

Impact of Dialysate Calcium Concentration on Clinical Outcomes in Incident Hemodialysis Patients

AbstractThe association between dialysate calcium (DCa) concentration and mortality in hemodialysis (HD) patients is controversial. In this study, we evaluated the impact of DCa concentration on mortality in incident HD patient.Incident HD patients were selected from the Clinical Research Center registry—a prospective cohort study on dialysis patients in Korea. Patients were categorized into 3 groups according to the prescribed DCa concentration at the time of enrollment. High DCa was defined as a concentration of 3.5 mEq/L, mid-DCa as 3.0 mEq/L, and low DCa as 2.5 to 2.6 mEq/L. The primary outcome was all-cause mortality and secondary outcomes were cardiovascular or infection-related hospitalization.A total of 1182 patients with incident HD were included. The number of patients in each group was 182 (15.4%) in high DCa group, 701 (59.3%) in the mid-DCa group, and 299 (25.3%) in the low DCa group. The median follow-up period was 16 months. The high DCa group had a significantly higher risk of all-cause mortality compared with the mid-DCa group (hazard ratio [HR] 2.23, 95% confidence interval [CI] 1.28–3.90, P = 0.005) and the low DCa group (HR 3.67, 95% CI 1.78–7.55, P < 0.001) after adjustment for clinical variables. The high DCa group was associated with higher risk of cardiovascular and infection-related hospitalization compared with the low DCa group (HR 3.25, 95% CI 1.53–6.89, P = 0.002; and HR 2.77, 95% CI 1.29–5.94, P = 0.009, respectively). Of these 1182 patients, 163 patients from each group were matched by propensity scores. In the propensity score matched analysis, the high DCa group had a significantly higher risk of all-cause mortality compared with the mid-DCa group (HR 2.52, 95% CI 1.04–6.07, P = 0.04) and the low DCa group (HR 4.25, 95% CI 1.64–11.03, P = 0.003) after adjustment for clinical variables.Our data showed that HD using a high DCa was a significant risk factor for all-cause mortality and cardiovascular or infection-related hospitalization in incident HD patients.

Serum Gamma-Glutamyltransferase Levels Predict Mortality in Patients With Peritoneal Dialysis.

Abstract Serum gamma-glutamyltransferase (GGT) level has been considered marker of oxidative stress as well as liver function. Serum GGT level has been reported to be associated with the mortality in hemodialysis patients. However, it is not well established whether serum GGT level is associated with all-cause mortality in peritoneal dialysis (PD) patients. The aim of this study was to determine the association between serum GGT levels and all-cause mortality in PD patients. PD patients were included from the Clinical Research Center registry for end-stage renal disease cohort, a multicenter prospective observational cohort study in Korea. Patients were categorized into 3 groups by tertile of serum GGT levels as follows: tertile 1, GGT < 16 IU/L; tertile 2, GGT = 16 to 27 IU/L; and tertile 3, GGT > 27 IU/L. Primary outcome was all-cause mortality. A total of 820 PD patients were included. The median follow-up period was 34 months. Kaplan–Meier analysis showed that the all-cause mortality rate was significantly different according to tertiles of GGT (P = 0.001, log-rank). The multivariate Cox regression analysis showed that higher tertiles significantly associated with higher risk for all-cause mortality (tertile 2: hazard ratio [HR] 2.08, 95% confidence interval [CI], 1.17–3.72, P = 0.013; tertile 3: HR 1.83, 95% CI, 1.04–3.22, P = 0.035) in using tertile 1 as the reference group after adjusting for clinical variables. Our study demonstrated that high serum GGT levels were an independent risk factor for all-cause mortality in PD patients. Our findings suggest that serum GGT levels might be a useful biomarker to predict all-cause mortality in PD patients.

Contrast Volume/Raw eGFR Ratio for Predicting Contrast-Induced Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Intervention for Myocardial Infarction

Background: Considering that contrast medium is excreted through the whole kidney in a similar manner to drug excretion, the use of raw estimated glomerular filtration rate (eGFR) rather than body surface area (BSA)-normalized eGFR is thought to be more appropriate for evaluating the risk of contrast-induced acute kidney injury (CI-AKI). Methods: This study included 2,189 myocardial infarction patients treated with percutaneous coronary intervention. Logistic regression analysis was performed to identify the independent risk factors. We used receiver-operating characteristic (ROC) curves to compare the ratios of contrast volume (CV) to eGFR with and without BSA normalization in predicting CI-AKI. Results: The area under the curve (AUC) of the ROC curve for the model including all the significant variables such as diabetes mellitus, left ventricular ejection fraction, preprocedural glucose, and the CV/raw modification of diet in renal disease (MDRD) eGFR ratio was 0.768 [95% confidence interval (CI), 0.720-0.816; p < 0.001]. When the CV/raw MDRD eGFR ratio was used as a single risk value, the AUC of the ROC curve was 0.650 (95% CI, 0.590-0.711; p < 0.001). When the CV/MDRD eGFR ratio with BSA normalization ratio was used, the AUC of the ROC curve further decreased to 0.635 (95% CI, 0.574-0.696; p < 0.001). The difference between the two AUCs was significant (p = 0.002). Conclusions: Raw eGFR is a better predictor for CI-AKI than BSA-normalized eGFR.

Serum β2-Microglobulin Predicts Mortality in Peritoneal Dialysis Patients: A Prospective Cohort Study

Background/Aims: β2-Microglobulin (β2-M) is a surrogate marker of middle-molecule uremic toxins and is associated with mortality in chronic hemodialysis patients. However, the impact of serum β2-M levels on mortality in peritoneal dialysis (PD) patients is uncertain. The purpose of this study was to examine the association of serum β2-M levels with all-cause mortality in PD patients. Methods: A total of 771 PD patients were selected from the Clinical Research Center registry for end-stage renal disease cohort in Korea. Patients were categorized into 3 groups by tertiles of serum β2-M levels. The primary outcome was all-cause mortality. Results: The median value of serum β2-M was 23.6 mg/l (interquartile range 14.8-33.4 mg/l), and the median follow-up period was 39 months. The Kaplan-Meier analysis showed that the all-cause mortality rate was significantly different according to tertiles of serum β2-M in PD patients (p = 0.03, log-rank). Multivariate Cox proportional analysis showed that the hazards ratio for all-cause mortality was 1.02 (95% CI 1.01-1.04, p = 0.006) per 1 mg/l increase in β2-M after adjustment for multiple confounding factors that relate to malnutrition and inflammation marker. However, serum β2-M was not associated with all-cause mortality after adjustment for residual renal clearance. Conclusions: These results are supportive of the potential role of the serum β2-M level as a predictor of mortality in PD patients.

HDL Cholesterol Level Is Associated with Contrast Induced Acute Kidney Injury in Chronic Kidney Disease Patients Undergoing PCI

Chronic kidney disease (CKD) is a significant risk factor for contrast induced acute kidney injury (CI-AKI) after percutaneous coronary intervention (PCI). This study included 1592 CKD patients extracted from a prospective multicenter, all comer-based registry of patients undergoing PCI. In multivariate logistic analysis for CI-AKI development, a significant linear trend was observed between the quartiles of HDL-C (quartile 1 vs. 2: odds ratio [OR], 0.716; 95% confidence interval [CI], 0.421–1.219; quartile 1 vs. 3: OR, 0.534; 95% CI, 0.301–0.947; quartile 1 vs. 4: OR, 0.173; 95% CI, 0.079–0.377; P for trend < 0.001). HDL-C quartiles were also negatively correlated with the incidence of CI-AKI; 19.0%, 12.1%, 8.7%, and 3.7% for quartile 1(Q1) (<34 mg/dL), Q2 (34–40 mg/dL), Q3 (40–48 mg/dL), and Q4 (>48 mg/dL) respectively (P < 0.001 overall and for the trend). Multivariate Cox regression analysis for the long term mortality, the highest HDL-C quartile was associated with decreased mortality compared with the lowest HDL-C quartile (hazard ratio [HR] 0.516, 95% CI, 0.320–0.832, P = 0.007). Our study suggests more intensive strategies should be considered for preventing CI-AKI in CKD patients with low serum HDL-C level who is planned for PCI.