Tae Ik Chang

Renal outcomes in patients with type 2 diabetes with or without coexisting non-diabetic renal disease

AIMS We sought not only to determine the independent predictors of non-diabetic renal disease (NDRD) but also to investigate the impact of NDRD on renal outcomes in patients with type 2 diabetes who underwent renal biopsy and were followed-up longitudinally. METHODS The present study was conducted by reviewing the medical records of 119 type 2 diabetic patients who underwent renal biopsy at Yonsei University Health System from January 1988 to December 2008. RESULTS Renal biopsy findings declared that 43 patients (36.1%) had diabetic nephropathy alone, 12 (10.1%) had NDRD superimposed on diabetic nephropathy, and 64 (53.8%) had only NDRD. On multivariate analysis, the absence of diabetic retinopathy, higher hemoglobin levels, and shorter duration of diabetes were independent predictors of NDRD in these patients. During the follow-up period, end-stage renal disease (ESRD) developed in 33 patients (27.7%). On multivariate Cox regression, higher serum creatinine levels, higher systolic blood pressure, longer duration of diabetes, and the presence of diabetic nephropathy were identified as significant independent predictors of ESRD. When the presence of diabetic retinopathy was included in the multivariate model, higher serum creatinine levels, higher systolic blood pressure, and the presence of retinopathy were shown to be independent predictors of ESRD. CONCLUSIONS Since diabetic patients with NDRD have significantly better renal outcomes compared to patients with biopsy-proven diabetic nephropathy, it is important to suspect, identify, and manage NDRD as early as possible, especially in type 2 diabetic patients with short duration of diabetes and those without diabetic retinopathy or anemia.

Uric acid is associated with the rate of residual renal function decline in peritoneal dialysis patients

BACKGROUND Uric acid (UA) is known to play a pathogenic role in chronic kidney disease (CKD). However, its effect in end-stage renal disease (ESRD) has not yet been elucidated. We explored the prevalence of hyperuricaemia and the relationship between UA and residual renal function (RRF) in peritoneal dialysis (PD) patients. METHODS The subjects of this study were 134 PD patients who started dialysis at the Yonsei University Health System between January 2000 and December 2005. Timed urine collections were performed within 1 month of PD commencement and at 6-month intervals thereafter. The slope of decline of RRF over time was calculated by linear regression analysis of serial urinary urea and creatinine clearances for each patient. Biochemical and clinical data at the time of initial urine collection were considered as baseline. RESULTS At baseline, 32.8% of the PD patients had hyperuricaemia (UA >or=7.0 mg/dl). A significant majority of patients with hyperuricaemia were diabetic (P = 0.02). Hypertensive patients had a higher UA level (P = 0.002) compared to normotensive patients. The overall reduction rate of RRF in hyperuricaemic patients was significantly higher than in the normouricaemic group (P = 0.001). In the multiple linear regression analysis, hyperuricaemia and history of DM showed a significant negative correlation with the reduction rate of RRF after adjusting for demographic data, comorbid conditions, body mass index, baseline RRF and medications (P = 0.001). CONCLUSIONS Hyperuricaemia is common among PD patients and is significantly associated with the rate of decline of RRF.

Clinical Features and Outcomes of IgA Nephropathy with Nephrotic Syndrome

BACKGROUND AND OBJECTIVES Nephrotic syndrome (NS) is a rare manifestation of IgA nephropathy (IgAN). Clinical characteristics and long-term outcomes of this condition have not yet been explored. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A multicenter observational study was conducted between January 2000 and September 2010 in 1076 patients with biopsy-proven IgAN from four medical centers in Korea. The primary outcome was a doubling of the baseline serum creatinine concentration. RESULTS Of the 1076 patients, 100 (10.2%) presented with NS; complete remission (CR), partial remission (PR), and no response (NR) occurred in 48 (48%), 32 (32%), and 20 (20%) patients, respectively. During the median follow-up of 45.2 months, 24 patients (24%) in the NS group reached the primary endpoint compared with 63 (7.1%) in the non-NS group (P<0.001). The risk of reaching the primary endpoint was significantly higher in the PR (P=0.04) and NR groups (P<0.001) than in the CR group. Among patients with NS, 24 (24%) underwent spontaneous remission (SR). SR occurred more frequently in female patients and in patients with serum creatinine levels ≤1.2 mg/dl and a >50% decrease in proteinuria within 3 months after NS onset. None of the patients with SR reached the primary endpoint and they had fewer relapses during follow-up. CONCLUSIONS This study demonstrated that the prognosis of NS in IgAN was not favorable unless PR or CR was achieved. In addition, SR was more common than expected, particularly in patients with preserved kidney function and spontaneous decrease in proteinuria shortly after NS onset.

EARLY CATHETER REMOVAL IMPROVES PATIENT SURVIVAL IN PERITONEAL DIALYSIS PATIENTS WITH FUNGAL PERITONITIS: RESULTS OF NINETY-FOUR EPISODES OF FUNGAL PERITONITIS AT A SINGLE CENTER

♦ Background: Fungal peritonitis (FP) is an uncommon but serious complication of peritoneal dialysis (PD) and is associated with high morbidity and mortality. Although previous studies have demonstrated that abdominal pain and catheter in situ are associated with mortality in FP patients, the effect of early catheter removal on mortality remains largely unexplored. In this study, therefore, we not only determine the risk factors for mortality but also investigate the effect of immediate catheter removal on mortality in PD patients with FP. ♦ Patients and Methods: This retrospective study was conducted on 94 episodes of FP in 1926 patients that underwent PD at Yonsei University Health System from January 1992 to December 2008. Data including demographic characteristics, laboratory and clinical findings, management, and outcome were collected from medical records. ♦ Results: Among a total of 2361 episodes of peritonitis, there were 94 episodes of FP in 92 patients, which accounted for 4.0% of all peritonitis episodes and occurred in 4.8% of patients. Mean age of patients was 52.1 years and mean duration of PD before contracting FP was 46.1 months. The presenting symptoms included turbid dialysate (93.6%), abdominal pain (84.0%), and fever (66.0%). Intestinal obstruction was complicated in 39 episodes (41.5%). 75% of FP was caused by Candida species, among which Candida albicans was the most common pathogen, accounting for 41.5% of all episodes of FP. The PD catheter was removed within 24 hours in 39 patients (41.5%), whereas catheter removal was performed between 2 and 9 days after the diagnosis of FP in 42 patients (44.7%). 27 patients (28.7%) died as a result of FP, 59 patients (62.8%) required a change to hemodialysis, and PD was resumed in 8 episodes (8.5%). In addition, the mortality rate was significantly higher in patients with delayed catheter removal (13/41, 31.7%) compared to patients with catheter removal within 24 hours (5/39, 12.8%) (p < 0.01). Multivariate logistic regression analysis revealed that delayed catheter removal, the presence of intestinal obstruction, and higher white blood cell counts in the blood and in the PD effluent were independently associated with mortality in FP patients. ♦ Conclusion: These results suggest that immediate catheter removal (i.e., within 24 hours after the diagnosis of FP) is mandatory in PD patients with FP.

Apoptosis occurs differentially according to glomerular size in diabetic kidney disease

BACKGROUND Apoptosis, which is involved in the process of mesangial cell and podocyte loss in diabetic nephropathy, is known to be regulated by protein kinase B/Akt (Akt). A number of studies have therefore investigated the activity of Akt under diabetic conditions, but the results have not been consistent. In this study, we hypothesized that apoptosis may occur differentially and that Akt may be differentially activated according to glomerular size in diabetic kidney disease. METHODS Fifty male Sprague-Dawley rats were injected intraperitoneally with diluent (C, n = 25) or streptozotocin (DM, n = 25). After 3 months, glomeruli were isolated using sieves with pore sizes of 250, 150, 125 and 75 μm and then classified into large glomeruli (on the 125-μm sieve, LG) and small glomeruli (on the 75-μm sieve, SG) groups. Western blot analyses for phospho-Akt, apoptosis-related molecules (Bax, Bcl-2, active fragments of Caspase-3 and phospho-p53) and cyclin-dependent kinase inhibitors were performed. CONCLUSIONS The numbers of total cells and podocytes in isolated glomeruli were determined using transmission electron microscopy. Akt phosphorylation was significantly decreased in DM-LG, while it was significantly increased in DM-SG (P < 0.05). The ratio of Bax/Bcl-2 protein expression and active fragments of Caspase-3 and phospho-p53 protein expression were significantly increased in DM-LG compared to DM-SG and C-SG (P < 0.001 and P < 0.01, respectively). In contrast, the expression of p27(Kip1) and p21(Cip1) was significantly increased in DM-SG compared to DM-LG and C-SG (P < 0.05). The numbers of total glomerular cells and podocytes were significantly decreased in DM-LG (P < 0.05). In conclusion, these data show differential expression of Akt activity and apoptosis-related molecules according to glomerular size in diabetic nephropathy, suggesting that apoptosis may be more operative in more hypertrophic glomeruli, resulting in fewer glomerular cells and podocytes in diabetic nephropathy.

Metabolic syndrome predicts mortality in non-diabetic patients on continuous ambulatory peritoneal dialysis

BACKGROUND Metabolic syndrome is associated with higher morbidity and mortality in the general population, but the corresponding effects in patients on dialysis have not been clearly defined. In this study, we prospectively investigated the effect of metabolic syndrome and its individual components on outcome in non-diabetic peritoneal dialysis (PD) patients. Method. The study subjects included 106 stable non-diabetic PD patients who had been on PD for >3 months. We measured baseline characteristics, blood pressure, fasting blood glucose, lipid profiles and high-sensitivity CRP (hsCRP), and defined metabolic syndrome using the modified National Cholesterol Education Program (Adult Treatment Panel III) criteria. Mortality, technical failure and hospitalization were evaluated during the follow-up period. RESULTS Metabolic syndrome was present in 50 patients (47.2%), and these showed higher baseline hsCRP levels (0.67; 95% CI: 0.50-0.94 versus 1.78 mg/dl; 95% CI: 1.21-2.57; P < 0.001). Patients with metabolic syndrome experienced significantly lower 5-year survival rates than patients without (90% versus 67%, P = 0.02), although these groups did not differ in peritonitis rates, technical failure or hospitalization. A Cox proportional hazards analysis identified the following as predictors of mortality: metabolic syndrome (RR: 3.39; 95% CI: 1.16-9.94; P = 0.02), baseline albumin (RR: 0.06; 95% CI: 0.01-0.30; P = 0.001) and baseline hsCRP levels (RR: 1.14; 95% CI: 1.07-1.22; P < 0.001). CONCLUSION Metabolic syndrome is prevalent and is a risk factor influencing long-term survival in non-diabetic PD patients.

Hyponatremia as a Predictor of Mortality in Peritoneal Dialysis Patients

Background and Aim Hyponatremia is common in patients with chronic kidney disease and is associated with increased mortality in hemodialysis patients. However, few studies have addressed this issue in peritoneal dialysis (PD) patients. Methods This prospective observational study included a total of 441 incident patients who started PD between January 2000 and December 2005. Using time-averaged serum sodium (TA-Na) levels, we aimed to investigate whether hyponatremia can predict mortality in these patients. Results Among the baseline parameters, serum sodium level was positively associated with serum albumin (β = 0.145; p = 0.003) and residual renal function (RRF) (β = 0.130; p = 0.018) and inversely associated with PD ultrafiltration (β = −0.114; p = 0.024) in a multivariable linear regression analysis. During a median follow-up of 34.8 months, 149 deaths were recorded. All-cause death occurred in 81 (55.9%) patients in the lowest tertile compared to 37 (25.0%) and 31 (20.9%) patients in the middle and highest tertiles, respectively. After adjusting for multiple potentially confounding covariates, increased TA-Na level was associated with a significantly decreased risk of all-cause (HR per 1 mEq/L increase, 0.79; 95% CI, 0.73–0.86; p<0.001) and infection-related (HR per 1 mEq/L increase, 0.77; 95% CI, 0.70–0.85; p<0.001) deaths. Conclusions This study showed that hyponatremia is an independent predictor of mortality in PD patients. Nevertheless, whether correcting hyponatremia improves patient survival is unknown. Future interventional studies should address this question more appropriately.

Insulin resistance and lower plasma adiponectin increase malignancy risk in nondiabetic continuous ambulatory peritoneal dialysis patients.

End-stage renal disease patients have a higher risk for developing cancer. Although several causes for this increased risk have been proposed, the risk factors for cancer development in this population have not been elucidated. The aim of this study was to determine whether metabolic derangements, including insulin resistance and altered adipokines, increase the risk of developing malignancies in peritoneal dialysis (PD) patients, who are vulnerable to metabolic disorders because of excessive glucose absorbed from the dialysate. Study subjects comprised 106 nondiabetic PD patients who had been on PD for a minimum of 3 months with no overt malignancy. Baseline anthropometry, fasting glucose, insulin, and adiponectin were measured. The development of malignancy was evaluated during the follow-up period. During the mean follow-up of 47.0 ± 23.7 months, malignancy occurred in 15 patients (14.2%). The most common site of cancer was the kidney (26.7%), followed by thyroid (13.3%) and stomach (13.3%). Baseline insulin levels and homeostasis model assessment of insulin resistance were significantly higher, whereas plasma adiponectin levels were significantly lower, in patients who developed malignancy. Cox proportional hazards analysis revealed that insulin levels, homeostasis model assessment of insulin resistance, and lower adiponectin were independent predictors of malignancy. These findings demonstrate that insulin resistance and lower adiponectin levels could be risk factors for malignancy in nondiabetic PD patients.

High Peritoneal Transport Status is Not an Independent Risk Factor for High Mortality in Patients Treated with Automated Peritoneal Dialysis

We undertook this study to elucidate whether baseline peritoneal membrane transport characteristics are associated with high mortality in incident automated peritoneal dialysis (APD) patients. This retrospective study includes 117 patients who started APD at Yonsei University Health System from 1996 to 2008 and had a PET within 3 months of APD initiation. High transporters were significantly older and had a higher incidence of cardiovascular disease. Patient survival for years 1, 3, and 5 were 85%, 64%, and 35% for high transporter and 94%, 81%, and 68% for non-high transporter group (P<0.01). Multivariate analysis revealed that age, diabetes, cardiovascular disease, serum albumin level, and residual renal function were independently associated with high mortality in APD patients. In contrast, high transport status was not a significant predictor for mortality in this population when the other covariates were included. Even though high transport was significantly associated with mortality in the univariate analysis, its role seemed to be influenced by other comorbid conditions. These findings suggest that the proper management of these comorbid conditions, as well as appropriate ultrafiltration by use of APD and/or icodextrin, must be considered as protective strategies to improve survival in peritoneal dialysis patients with high transport.

(The) effect of statin on epithelial-mesenchymal transition in peritoneal mesothelial cells

Background Statins have recently been highlighted for their pleiotropic actions distinct from cholesterol-lowering effects. Despite this interest, it is currently unknown whether statin therapy inhibits peritoneal dialysis (PD)-related epithelial-mesenchymal transition (EMT). Methods In vitro, human peritoneal mesothelial cells (HPMCs) were exposed to 5.6 mM glucose (NG) or 100 mM glucose (HG) with or without simvastatin (1 µM). In vivo, PD catheters were inserted into 32 Sprague-Dawley rats, and saline (C, n = 16) or 4.25% peritoneal dialysis fluid (PDF) (PD, n = 16) was infused for 4 weeks. Eight rats from each group were treated with 5 mg/kg/day of simvastatin intraperitoneally. Changes in the protein expression of EMT markers such as E-cadherin, α-SMA, Snail, and fibronectin in HPMCs and the peritoneum were evaluated by Western blot analysis and immunofluorescence or immunohistochemical staining. We also explored whether activation of the mevalonate pathway and its downstream small GTPases were involved in dialysis-related peritoneal EMT and could be inhibited by statin treatment. Results Compared to NG cells, E-cadherin expression was significantly decreased, while α-SMA, Snail, and fibronectin expression were significantly increased in HPMCs exposed to HG, and these changes were abrogated by simvastatin (p<0.05). In addition, the cobblestone-like appearance of normal HPMCs was converted into a fibroblast-like morphology after HG treatment, which was reversed by simvastatin. These EMT-like changes were also observed in HPMCs treated with geranyl-geranyl pyrophosphate (5 µM). HG significantly increased the protein expression of RhoA and Rac1 in the membrane fractions, and these increases were ameliorated by simvastatin (p<0.05). In PD rats, E-cadherin in the peritoneum was significantly decreased, whereas α-SMA, Snail, and fibronectin expression were significantly increased (p<0.05) compared to C rats. The thickness of the mesothelial layer in the peritoneum were also significantly greater in PD rats than in C rats (p<0.05). These changes of the peritoneum in PD rats were significantly attenuated by simvastatin. Conclusion This study demonstrated that PD-related EMT was mediated via the mevalonate pathway, and statin treatment inhibited the EMT changes in HG-treated HPMCs and PDF-stimulated PD rats. These findings suggest that statins may be a promising therapeutic strategy for preservation of peritoneal membrane integrity in long-term PD patients.