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Autosomal dominant polycystic kidney disease (ADPKD) is one of the main causes of end-stage renal disease (ESRD). Genetic information is of the utmost importance in understanding pathogenesis of ADPKD. Therefore, this study aimed to demonstrate the genetic characteristics of ADPKD and their effects on renal function in 749 Korean ADPKD subjects from 524 unrelated families. Genetic studies of PKD1/2 were performed using targeted exome sequencing combined with Sanger sequencing in exon 1 of the PKD1 gene and a multiple ligation probe assay. The mutation detection rate was 80.7% (423/524 families, 331 mutations) and 70.7% was novel. PKD1 protein-truncating (PKD1-PT) genotype was associated with younger age at diagnosis, larger kidney volume, lower renal function compared to PKD1 non-truncating and PKD2 genotypes. The PKD1 genotype showed earlier onset of ESRD compared to PKD2 genotype (64.9 vs. 72.9 years old, P PKD2 genotype had 0.2 times lower risk for reaching ESRD than PKD1-PT genotype (p = 0.037). In conclusion, our results suggest that genotyping can contribute to selecting rapid progressors for new emerging therapeutic interventions among Koreans.

Background Intrarenal renin-angiotensin system (RAS) is known to play the major role in the development of hypertension and renal progression in autosomal dominant polycystic kidney disease (ADPKD). Urinary angiotensinogen to creatinine ratio (AGT/Cr) was suggested as a novel biomarker to reflect intrarenal RAS activity. This study was performed to evaluate urinary AGT/Cr as a predictive biomarker for renal function decline in addition to imaging classification in a prospective ADPKD cohort. Methods From 2011 to 2016, a total of 364 ADPKD patients were enrolled in the prospective cohort called the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). Among them, a total of 207 subjects in chronic kidney disease stage 1–4 with baseline urinary AGT and total kidney volume and subsequent renal function follow-up data over more than 1 year were included in the analysis. Patients were defined as slow progressors (SP) if they are classified as 1A or 1B by imaging classification whereas rapid progressors (RP) if they are classified as 1C–1E. Patients were divided according to AGT/Cr quartiles and annual estimated glomerular filtration rate (eGFR) slope was compared among highest quartile (hAGT group) and the rest of quartiles (lAGT group). Patients were divided into 4 groups to evaluate the predictive value of urinary AGT/Cr in addition to imaging classification: SP/lAGT, SP/hAGT, RP/lAGT, and RP/hAGT. The Cox regression model was used to evaluate the hazard ratio (HR) between groups. Results The mean age was 45.9 years and 88.9% had hypertension. Baseline eGFR was 79.0 ± 28.4 mL/min/1.73 m2 and median height-adjusted total kidney volume was 788.2 (471.2; 1,205.2) mL/m. The patients in the hAGT group showed lower eGFR (72.4 ± 24.8 vs. 81.1 ± 29.2 mL/min/1.73 m2, P = 0.039), lower plasma hemoglobin (13.0 ± 1.4 vs. 13.7 ± 1.6 g/dL, P = 0.007), higher urinary protein to creatinine ratio (0.14 [0.09, 0.38] vs. 0.07 [0.04, 0.12] g/g, P = 0.007) compared to the lAGT group. The hAGT group was an independent risk factor for faster eGFR decline after adjusting for gender, RP, baseline eGFR, and other known risk factors. During median follow-up duration of 4.6 years, a total of 29 renal events (14.0%) occurred. The SP/hAGT group showed significantly higher risk of developing renal outcome compared to SP/lAGT group (HR, 13.4; 95% confidence interval, 1.282–139.324; P = 0.03). Conclusion Urinary AGT/Cr can be a useful predictive marker in the patients with relatively small ADPKD. Various biomarkers should be considered to define RP when implementing novel treatment in the patients with ADPKD., Graphical Abstract

Aims Cyst infection (CI) is a common problem in patients with autosomal dominant polycystic kidney disease (ADPKD). Localization is of great importance in CI. We describe the clinical experience with [18F] FDG-labeled white-blood cell (WBC) PET/CT in detecting CI in ADPKD. Methods 19 ADPKD patients (M:F = 7:12) suspected of having CI were enrolled in this prospective study. All underwent WBC-PET/CT and MRI or CT. The degree of their WBC accumulation was evaluated from the maximal standardized uptake value of cystic wall. Results CI was diagnosed in 14 cases [definite (n = 6), probable (n = 1), or possible (n = 7); kidney (n=11), or liver (n=3)]. There was no difference in fever or laboratory findings (White blood cell count, C-reactive protein, culture results, and eGFR). The blood culture was positive only in a subset of CI patients (n=4). Cyst fluid culture yielded bacterial growth in 80% of aspirates. WBC-PET/CT detected 64% of CI cases, whereas conventional imaging, 50%. WBC-PET/CT showed false-positive results in 2 of 5 cases with no CI. The reasons for false negatives with WBC-PET/CT were poor host immune reaction, low virulence, or prior antibiotic therapy. Hemorrhagic cysts were the most common cause of false positivity in WBC-PET/CT. However, WBC-PET/CT detected CI in 3 cases, in which the conventional imaging failed to find CI. Conclusions Clinical information may play little role in the diagnosis of CI. WBC-PET/CT can be used to detect CI with better sensitivity in ADPKD patients, circumventing the exposure to contrast media.

The absence of a positive family history (PFH) in 10%–25% of patients poses a diagnostic challenge for autosomal dominant polycystic kidney disease (ADPKD). In the Toronto Genetic Epidemiology Study of Polycystic Kidney Disease, 210 affected probands underwent renal function testing, abdominal imaging, and comprehensive PKD1 and PKD2 mutation screening. From this cohort, we reviewed all patients with and without an apparent family history, examined their parental medical records, and performed renal imaging in all available parents of unknown disease status. Subsequent reclassification of 209 analyzed patients revealed 72.2% (151 of 209) with a PFH, 15.3% (32 of 209) with de novo disease, 10.5% (22 of 209) with an indeterminate family history, and 1.9% (four of 209) with PFH in retrospect. Among the patients with de novo cases, we found two families with germline mosaicism and one family with somatic mosaicism. Additionally, analysis of renal imaging revealed that 16.3% (34 of 209) of patients displayed atypical PKD, most of which followed one of three patterns: asymmetric or focal PKD with PFH and an identified PKD1 or PKD2 mutation (15 of 34), asymmetric and de novo PKD with proven or suspected somatic mosaicism (seven of 34), or focal PKD without any identifiable PKD1 or PKD2 mutation (eight of 34). In conclusion, PKD without an apparent family history may be due to de novo disease, missing parental medical records, germline or somatic mosaicism, or mild disease from hypomorphic PKD1 and PKD2 mutations. Furthermore, mutations of a newly identified gene for ADPKD, GANAB, and somatic mosaicism need to be considered in the mutation-negative patients with focal disease.

Objective Adiponectin (ADPN) has antiatherogenic, anti-inflammatory, and insulin-sensitizing effects. Serum ADPN levels are increased in patients with chronic kidney diseases (CKD), and higher ADPN is paradoxically a predictor of mortality in these patients. The aim of this study was to determine the association between serum ADPN levels and protein–energy wasting (PEW) in predialysis CKD. Method We examined serum ADPN concentrations and PEW in 1303 patients from the KNOW-CKD (KoreaN Cohort Study for Outcome in Patients With Chronic Kidney Disease) study. PEW was defined as the presence of three or more of the following four indicators: serum albumin Results Among 1303 predialysis CKD patients, 72 (5.5%) had PEW. In multivariate logistic regression analysis, higher ADPN level was associated with PEW (odds ratio, 1.04; 95% confidence interval [CI], 1.01–1.08 by 1 μg/mL ADPN). The highest ADPN quartile was associated with PEW in comparison with the lowest quartile (odds ratio, 10.54; 95% CI, 1.28–86.74). In multiple linear regression with PEW indicators, ADPN was more strongly associated with UCE (β = −2.21; 95% CI, −4.13 to −0.28; R2 = 0.67). Conclusion High ADPN is independently associated with PEW. Among PEW indicators, serum ADPN is closely associated with UCE as an indirect measure of muscle mass.

♦ BackgroundFibroblast growth factor 23 (FGF23) is a phosphate regulating protein. Several studies demonstrated that elevated FGF23 is independently associated with mortality for early-stage chronic kidney disease and incident hemodialysis (HD) patients. However, little is known about the significance of elevated FGF23 in peritoneal dialysis (PD) patients. Here, we analyzed the association of FGF23 with cardiovascular (CV) events, all-cause mortality, residual renal function (RRF), and CV parameters in PD patients.♦ MethodsThe present study is a single-center, retrospective study. Patients who started PD at Seoul National University Hospital between January 2005 and July 2011 and whose baseline serum samples were available were enrolled. C-terminal FGF23 was measured. Subjects were divided into 2 groups; lower 2 tertiles (FGF23 ≤ 119.0 RU/mL) and top tertile (FGF23 > 119.0 RU/mL). The primary outcome was time to fatal or non-fatal CV events. In the subgroup analysis, the associations of FGF23 with aortic stiffness or with vascular calcification were analyzed.♦ResultsA total of 205 incident PD patients were analyzed. Mean duration of follow-up was 41.6 ± 20.0 months. The baseline median FGF23 level was 78.6 RU/mL (interquartile range [IQR], 34.1 – 155.0). At baseline, subjects in the higher FGF23 group were younger, and had a lower RRF, lower prevalence of diabetes mellitus (DM), and cerebrovascular disease. During follow-up, 22 of the 205 patients (10.7%) reached primary outcome. After adjustment for age, DM, pre-existing coronary artery disease, cerebrovascular disease, congestive heart failure, and left ventricular mass index, the higher FGF23 group exhibited significantly higher risk of primary outcome, compared with the lower group (hazard ratio [HR], 2.54; 95% confidence interval [CI], 1.05 – 6.12; p = 0.045). There were no significant differences in all-cause mortality and development of anuria between the 2 FGF23 groups. In the subgroup analysis, FGF23 groups were not associated with pulse wave velocity and abdominal aortic calcification score.♦ ConclusionElevated FGF23 is associated with higher risk of adverse CV outcome for incident PD patients.

The present study, entitled Trial on Education And Clinical outcomes for Home PD patients (TEACH), investigated the effect of frequent retraining at home on the outcomes of peritoneal dialysis (PD). TEACH is a multicentre, open-label, randomised, controlled trial with parallel arms. Patients starting PD were randomized into either the conventional retraining group (CG) or the frequent retraining group (FG). Patients in the FG were given more frequent home visits for retraining. The primary endpoint was exit site infection (ESI). Secondary endpoints were peritonitis, any PD-related infections, hospitalization, technique failure, and patient survival. A generalised estimating equations (GEE) approach was employed for the adjusted effect of training level on the outcomes. Cox regression was employed for peritonitis and other secondary outcomes. The subjects were randomised to either the FG (n = 51) or the CG (n = 53). Although the time of initial training did not differ between the 2 groups, the total time of training was longer and the frequency of training visits was higher in the FG. In the GEE model, the p-values for interactions between groups and time were significant for both ESI and any PD-related infections, suggesting that the event rates of the two groups significantly changed over time. The event rates for the FG decreased over time, and the event rates for the CG increased after month 12. In the older subgroup (age ≥ 60), frequent retraining had a significant effect in the risk reduction of the first episode of peritonitis (adjusted HR 0.01 [0.001–0.35], p = 0.01). Frequent retraining at home reduced the risk of PD-related infections.

Rationale & Objective Recent studies have yielded conflicting findings on the association between obesity and progression of chronic kidney disease (CKD). Few studies have evaluated whether metabolic abnormalities may accelerate the rate of progression of CKD. Study Design Prospective observational cohort study. Setting & Participants 1,940 participants from the Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease (KNOW-CKD) Predictors Obesity and metabolic abnormality. Obesity was defined as body mass index ≥ 25kg/m2. Metabolic abnormality was defined as the presence of 3 or more of the following 5 components: hypertension, fasting glucose level > 125mg/dL or the presence of type 2 diabetes, triglyceride level > 150mg/dL or use of lipid-lowering drugs, high-density lipoprotein cholesterol level ≤ 40mg/dL in men and ≤ 50mg/dL in women, and high-sensitivity C-reactive protein level > 1mg/L. Outcome A composite of a 50% decline in estimated glomerular filtration rate from the baseline value or end-stage kidney disease. Analytic Approach Multivariable cause-specific hazards models implemented to assess the association between obesity, metabolic abnormality, and CKD progression. Results During a mean follow-up of 3.1 years, the primary outcome occurred in 395 (20.4%) patients. In multivariable analyses, after adjustment for confounding factors, obesity and metabolic abnormality were significantly associated with 1.41-fold (95% CI, 1.08-1.83; P=0.01) and 1.38-fold (95% CI, 1.03-1.85; P=0.03) increased risk for adverse renal outcomes, respectively. Patients were categorized into 4 groups depending on the presence of obesity and metabolic abnormality. Compared with those with neither obesity nor metabolic abnormality, those with obesity and metabolic abnormality had a greater risk for CKD progression (HR, 1.53; P=0.03). Those with obesity without metabolic abnormality also had a higher rate of CKD progression (HR, 1.97; P=0.01). Limitations Observational study, limited power to detect cardiovascular disease outcomes, unmeasured confounders. Conclusions Both metabolic abnormality and obesity are associated with a significantly increased risk for CKD progression. Notably, obese patients without metabolic abnormality also have an elevated risk for CKD progression.

The clinical importance of serum hepcidin in non-dialysis chronic kidney disease (CKD) patients is unclear. The database of a large-scale multicentre prospective study in Korea of 2238 patients enrolled from 2011–2016 was analysed. After excluding patients with missing serum hepcidin (n = 125) and haemoglobin (n = 23) levels, the study included 2090 non-dialysis CKD patients. Markers of inflammation and iron status were positively associated with serum hepcidin level, regardless of CKD stage. However, estimated glomerular filtration rate was inversely associated with serum hepcidin level, particularly in patients with CKD stages 3b–5 but not in those with CKD stages 1–3a. Use of erythropoiesis-stimulating agents was associated with increased serum hepcidin levels, particularly in patients with CKD stages 3b–5 but not in those with CKD stages 1–3a, and serum hepcidin levels positively correlated with the dose of erythropoiesis-stimulating agent. These findings suggest that serum hepcidin may be a uremic toxin and play an important role in erythropoietin resistance. However, future prospective studies are needed to confirm our results.

Background In patients with autosomal dominant polycystic kidney disease (ADPKD), malnutrition may develop as renal function declines and the abdominal organs become enlarged. We investigated the relationship of intra-abdominal mass with nutritional status. Methods This cross-sectional study was performed at a tertiary hospital outpatient clinic. Anthropometric and laboratory data including serum creatinine, albumin, and cholesterol were collected, and kidney and liver volumes were measured. Total kidney and liver volume was defined as the sum of the kidney and liver volumes and adjusted by height (htTKLV). Nutritional status was evaluated by using modified subjective global assessment (SGA). Results In a total of 288 patients (47.9% female), the mean age was 48.3 ± 12.2 years and the mean estimated glomerular filtration rate (eGFR) was 65.3 ± 25.3 mL/min/1.73 m2. Of these patients, 21 (7.3%) were mildly to moderately malnourished (SGA score of 4 and 5) and 63 (21.7%) were at risk of malnutrition (SGA score of 6). Overall, patients with or at risk of malnutrition were older, had a lower body mass index, lower hemoglobin levels, and poorer renal function compared to the well-nourished group. However, statistically significant differences in these parameters were not observed in female patients, except for eGFR. In contrast, a higher htTKLV correlated with a lower SGA score, even in subjects with an eGFR ≥45 mL/min/1.73 m2. Subjects with an htTKLV ≥2340 mL/m showed an 8.7-fold higher risk of malnutrition, after adjusting for age, hemoglobin, and eGFR. Conclusions Nutritional risk was detected in 30% of ambulatory ADPKD patients with relatively good renal function. Intra-abdominal organomegaly was related to nutritional status independently from renal function deterioration. Electronic supplementary material The online version of this article (doi:10.1186/s12882-016-0434-0) contains supplementary material, which is available to authorized users.

BACKGROUND Autosomal dominant polycystic kidney disease (ADPKD) volumetry is an important marker for evaluating the progression of disease. Three-dimensional (3D) volumetry is generally more timesaving than 2D volumetry, but its reliability and accuracy are uncertain. METHODS Small and large phantoms simulating polycystic kidneys and 20 patients with ADPKD underwent magnetic resonance imaging (MRI) volumetry. We evaluated the total kidney volume (TKV) and total cyst volume (TCV) using a novel 3D volumetry program (XelisTM) and compared 3D volumetry data with the conventional 2D method (the reference volume values). After upload and threshold setting, the other organs surrounding the kidney were removed by picking and sculpting. The novel method involves drawing of the kidney or cyst and automatic measurement of kidney volume and cyst volume in 3D images. RESULTS The 3D volume estimation of the small and large phantoms differed from the actual values by 6.9% and -8.2%, respectively, for TKV and by 2.1% and 1.4% for TCV. In ADPKD patients, the intra-reader reliability of 3D volumetry was 30 ± 180 mL (1.3 ± 10.3%) and 25 ± 113 mL (1.2 ± 9.4%), respectively, for TKV and TCV. Correlation between 3D volumetry and 2D volumetry of TKV and TCV resulted in a high correlation coefficient and a regression slope approaching 1.00 (r = 0.97 - 0.98). The mean of the volume percentage differences for 3D vs. 2D for TKV : TCV were -6.0 ± 8.9% : 2.0 ± 11.8% in large ADPKD and -16.1 ± 10.4% : 13.2 ± 21.9% in small ADPKD. CONCLUSION Our study showed that 3D volumetry has reliability and accuracy compared with 2D volumetry in ADPKD. 3D volumetry is more accurate for TCV and large ADPKD.

Introduction Although a latent tuberculosis (TB) infection is a risk factor for active TB, the diagnosis of latent TB infection is difficult in end-stage renal disease patients. Patients and Methods We retrospectively compared the results of the QuantiFERON-TB (QFT) test and the tuberculin skin test in patients on the waiting list for kidney transplantation (KT), and investigated whether the QFT test can predict TB development in KT recipients in an intermediate-TB-burden country. Results The incidence of post-KT TB was 283 cases/100,000 patient-years among 1274 KT recipients at the Seoul National University Hospital. The overall standardized incidence ratio of TB was 4.358 compared with the general population. A past history of TB infection, smoking history, myocardial infarction after KT, and pneumocystis infection were significant predictors of subsequent TB development (adjusted odds ratios were 3.618, 2.959, 9.993, and 5.708, respectively). Among the 129 recipients who had the QFT test, 42 patients (32.5%) had positive a QFT. At a median follow-up of 8.4 ± 6.8 months, 1 patient with positive QFT results developed TB after KT, and 1 of the 87 patients with negative QFT results developed TB after KT. In both of these 2 cases, active TB developed despite isoniazid prophylaxis. Among 272 patients on the waiting list for KT, the tuberculin skin test and QFT were positive in 22.8% and 35.3%, respectively. The degree of agreement between the 2 tests was poor (κ = 0.352). Conclusions The QFT test did not predict subsequent short-term TB development. Furthermore, a long-term and larger-scale study is needed to confirm our results.

In chronic kidney disease (CKD), overweight and mild obesity have shown the lowest cardiovascular (CV) risk. However, central obesity has been directly associated with CV risk in these patients. This bidirectional relationship of body mass index (BMI) and central obesity prompted us to evaluate CV risk based on a combination of BMI and waist-to-hip ratio (WHR) in nondialysis CKD patients. We included 1078 patients with CKD stage 2 through 5 (nondialysis) enrolled in a nationwide prospective cohort of Korea. Patients were divided into 3 groups by BMI (normal BMI, 18.5–22.9; overweight, 23.0–27.4; and obese, 27.5 and over kg/m 2 ) and were dichotomized by a sex-specific median WHR (0.92 in males and 0.88 in females). Coronary artery calcification (CAC) was determined by multislice computed tomography. CAC (score above 10 Agatston units) was found in 477 patients. Multivariate logistic regression analysis indicated that BMI was not independently associated with CAC. However, WHR showed an independent linear and significant association with CAC (odds ratio, 1.036; 95% confidence interval, 1.007-1.065 per 0.01 increase). Furthermore, when patients were categorized into 6 groups according to a combination of BMI and WHR, normal BMI but higher WHR had the highest risk of CAC compared with the normal BMI with lower WHR group (2.104; 1.074–4.121). Thus, a normal BMI with central obesity was associated with the highest risk of CAC, suggesting that considering BMI and WHR, 2 surrogates of obesity, can help to discriminate CV risk in Korean nondialysis CKD patients.

Objectives Cyst infection (CI) is a common problem in patients with autosomal dominant polycystic kidney disease (ADPKD) and the accurate detection of infected cysts is very important. We evaluated the diagnostic performance of fluorine-18 fluorodeoxyglucose-labeled white blood cell (WBC) PET/computed tomography (CT) for detection of infected cysts in patients with ADPKD. Patients and methods Seventeen patients with ADPKD (male : female, 6 : 11; age, 53±9 years) and suspected CI were enrolled in this prospective study. Patients were classified as having definite/probable/possible CI. All patients underwent WBC PET/CT within 2 days of starting antibiotic treatment. The degree of WBC accumulation was evaluated qualitatively by nuclear medicine physicians. The diagnostic performance of WBC PET/CT was evaluated by sensitivity, specificity, positive predictive values, and negative predictive values. These values were compared with those generated from CT scans and MRI. Results Seven patients were classified as having renal CI (definite 6, probable 1). In this group, WBC PET/CT showed six positive findings and one equivocal finding. Seven patients were diagnosed with possible infection. In this group, WBC PET/CT showed six negative findings and one indeterminate finding. The diagnostic performance of WBC PET/CT showed advantages over CT or MRI scans (sensitivity 85.7%, specificity 87.5%, positive predictive value 85.7%, negative predictive value 87.5%). Conclusion This prospective study shows that WBC PET/CT can provide an accurate diagnosis of CI in patients with ADPKD.

Pyruvate is an endogenous antioxidant and anti-inflammatory substance. The present study was implemented to investigate the protective effect of ethyl pyruvate (EP) against the development and progression of diabetic nephropathy in an in vivo and in vitro model. Diabetic rats were prepared by injecting streptozotocin (65 mg/kg). Those that developed diabetes after 72 h were treated with EP (40 mg/kg) intraperitoneally. Diabetic rats without pyruvate treatment and nondiabetic rats were used for control. As an in vitro experiment, rat mesangial cells cultured primarily from Sprague-Dawley rats were treated in high-glucose (HG; 50 mM) or normal-glucose (NG; 5 mM) conditions and with or without pyruvate. Pyruvate-treated diabetic rats exhibited decreased albuminuria and attenuated NADPH-dependent reactive oxygen species generation. Immunohistochemistry showed reduced laminin, type IV collagen, and fibronectin deposition in the glomeruli compared with nontreated diabetic rats. Parallel changes were shown in tissue mRNA and protein expression levels of monocyte chemoattractant protein-1, transforming growth factor-β1, laminin, fibronectin, and type IV collagen in the kidney. Concordantly, protective effects were also exhibited in the mesangial cell culture system. These findings suggest that pyruvate protects against kidney injury via NADPH oxidase inhibition. The present study established that activation of NADPH oxidase plays a crucial role in diabetes-induced oxidative stress, glomerular hypertrophy, and ECM molecule expression. Pyruvate exhibited a renoprotective effect in the progression of experimental diabetic nephropathy. Future research is warranted to investigate the protective mechanism of pyruvate more specifically in relation to NADPH oxidase in diabetic nephropathy.

Higher levels of coronary artery calcification score (CACS) are associated not only with an increased risk for cardiovascular death, but also with lower glomerular filtration rates (GFRs). However, its role in renal disease progression in patients has not been elucidated.We evaluated the change of estimated GFR in 279 nondialytic outpatients, who had undergone computed tomographic coronary angiography and follow-up over a period of 3 months.The mean age of the participants was 57.7 ± 10.5 years, and the mean GFR was 88.2 ± 15.7 mL/min/1.73 m(2). Although there was no difference in baseline GFR between the CACS ≤ 200 AU group (n = 240) and the CACS200 AU group (n = 39), the latter group had a lower level of final GFR and higher annual reduction rate of GFR than the former group after an observation period of 13.1 ± 5.97 months. After adjusting for confounding variables, including age, gender, baseline GFR, albumin, and proteinuria, high levels of CACS showed an independent association with an annual reduction rate of GFR (r = -0.142, P = .048).The results suggest that CACS was related to an annual decrease in GFR and may predict the faster decline in GFR in patients with symptoms requiring computed tomographic coronary angiography.

The pharmacokinetics (PK) of ceftazidime after intravenous (i.v.) administration during automated peritoneal dialysis (APD) and their dependence on peritoneal membrane transport are the targets of the present study. Eleven patients receiving a single i.v. dose of ceftazidime (15 mg/kg of body weight) (seven males, median [interquatile] age, 59 [36 to 62]) were recruited. Serum and dialysate samples were collected at the beginning, middle, and end of each of the five dwells during a 24-h period, with dwells 1, 2, and 3 using an automated cycler (designated on-cycler) and dwells 4 and 5 being manual exchanges (designated off-cycler), together with urine collection during the same period. Population PK analysis was employed to estimate the PK parameters. Peritoneal equilibration tests were performed for all patients, and correlations between peritoneal clearance (CL PD ) for ceftazidime and dialysate-to-plasma ratios for creatinine (D/P cr ) were obtained using the Spearman's product correlation coefficient (ρ). Ceftazidime renal clearance (CL renal ) was 0.052 ml/min/kg, and CL PD was 0.063 ± 0.050 ml/min/kg. CL PD for on- and off-cycler were 0.071 and 0.058 ml/min/kg ( P = 0.164), respectively. A significant correlation between CL PD and D/P cr was observed, with one outlier excluded, suggesting that CL PD for ceftazidime during APD is dependent upon the peritoneal small-solute transport rate. A model prediction yielded adequate serum and dialysate concentrations of ceftazidime throughout a 24-h period for sensitive organisms (MIC, 8 μg/ml) by either i.v. (at 15 mg/kg) or intraperitoneal (i.p.; at 20 mg/kg) administration during off-cycler dwells. The present study suggests that the i.v. administration of ceftazidime at 15 mg/kg or i.p. administration of ceftazidime at 20 mg/kg during a long dwell every 24 h can be recommended for treating systemic or intraperitoneal infections of APD patients.

Purpose Marginal grafts should be used more actively in Asian countries where deceased donor transplantation is unpopular. We modified a quantitative donor scoring system proposed by Nyberg and his colleagues and developed a donor scoring system in order to assess the quality of deceased donor grafts and their prognostic value as an initial effort to promote usage of marginal donors. Materials and Methods We retrospectively evaluated 337 patients. Results A scoring system was derived from six donor variables [age, 0-25; renal function, 0-4; history of hypertension, 0-4; Human Leukocyte Antigen (HLA) mismatch, 0-3; body weight, 0-1; cause of death, 0-3 points]. Donor grafts were stratified by scores: grade A, 0-10; grade B, 11-20; grade C, 21-30; and grade D, 31-40 points. Donor grades significantly correlated with estimated glomerular filtration rate (eGFR) at 6 months (A, 64.0 mL/min/1.73 m2; B, 57.0 mL/min/1.73 m2; C, 46.8 mL/min/1.73 m2; p < 0.001). The five-year graft survival rate was also lower in grade C than grade A (74% vs. 93%, p = 0.002). Donors in grade C and D were regarded as marginal donors. The proportion of marginal donors was much lower in Korea, compared with data from the United Network for Organ Sharing (15.2% vs. 29%). Conclusion Considering the scarcity of deceased donor kidneys and the relatively better graft outcome with lower grade-donors in Korea, it is worth increasing the usage of marginal grafts.

⋄ Objectives In vitro studies of peritoneal dialysis (PD) solutions demonstrated that a lactate-buffered fluid with neutral pH and low glucose degradation products (LF) has better biocompatibility than a conventional acidic lactate-buffered fluid (CF). However, few clinical trials have evaluated the long-term benefit of the biocompatible solution on residual renal function (RRF). To compare LF with CF, we performed a prospective, randomized study with patients starting PD. ⋄ Patients and Methods After 1-month run-in period, 91 new PD patients were randomized for 12 months of treatment with either LF (Balance: Fresenius Medical Care, Bad Homburg, Germany; n = 48) or CF (Stay•Safe: Fresenius; n = 43). We measured RRF, acid–base balance, peritoneal equilibration test, and adequacy of dialysis every 6 months after the run-in period. ⋄ Results After 12 months of treatment, the residual glomerular filtration rate (GFR) in patients using LF tended to be higher than that of patients on CF ( p = 0.057 by repeated-measures analysis of variance). We observed a significant difference in the changes of residual GFR between the two groups ( p = 0.009), a difference that was especially marked in the subgroup whose baseline residual GFR was more than 2 mL/min/1.73 m2. In addition, serum total CO2 levels were higher ( p = 0.001) and serum anion gap was lower ( p = 0.019) in the LF group. We observed no differences between groups for Kt/V, C-reactive protein, or normalized protein equivalent of nitrogen appearance. ⋄ Conclusions In incident PD patients with significant residual GFR, LF may better preserve RRF over a 12-month treatment period. Additionally, pH-neutral PD fluid may improve acid–base balance as compared with CF.

Adiponectin, a peptide hormone secreted from adipocytes, exerts anti-diabetic, anti-atherogenic, and anti-inflammatory properties. We aimed to determine the relationship between serum adiponectin levels and albuminuria, and evaluate determinant factors for serum adiponectin in patients with chronic kidney disease (CKD). In total, 1442 CKD patients were included and divided into three groups according to their albumin-to-creatinine ratios: patients with normoalbuminuria (N = 228), microalbuminuria (N = 444), and macroalbuminuria (N = 761). Serum adiponectin was specifically assayed with a commercially available enzyme-linked immunosorbent assay kit. Serum adiponectin was significantly higher in patients with macroalbuminuria than in those without macroalbuminuria (9.7 ± 6.0, 12.4 ± 9.0, and 14.9 ± 11.0 μg/mL in patients with normoalbuminuria, microalbuminuria, and macroalbuminuria, respectively). Univariate linear regression analysis showed that the serum adiponectin concentrations were correlated with age, the albumin-to-creatinine ratio, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, whereas they were negatively correlated with body mass index, the estimated glomerular filtration rate, and serum albumin and triglyceride levels. The stepwise regression multiple analysis showed that sex; the estimated glomerular filtration rate; body mass index; total cholesterol, high-density lipoprotein cholesterol, and triglyceride levels; and logarithm of the albumin-to-creatinine ratio were independently associated with the logarithm of serum adiponectin levels (r = 0.55, p

Renal disease variability in autosomal dominant polycystic kidney disease (ADPKD) is strongly influenced by the gene locus (PKD1 versus PKD2). Recent studies identified nontruncating PKD1 mutations in approximately 30% of patients who underwent comprehensive mutation screening, but the clinical significance of these mutations is not well defined. We examined the genotype-renal function correlation in a prospective cohort of 220 unrelated ADPKD families ascertained through probands with serum creatinine ≤1.4 mg/dl at recruitment. We screened these families for PKD1 and PKD2 mutations and reviewed the clinical outcomes of the probands and affected family members. Height-adjusted total kidney volume (htTKV) was obtained in 161 affected subjects. Multivariate Cox proportional hazard modeling for renal and patient survival was performed in 707 affected probands and family members. Overall, we identified pathogenic mutations in 84.5% of our families, in which the prevalence of PKD1 truncating, PKD1 in-frame insertion/deletion, PKD1 nontruncating, and PKD2 mutations was 38.3%, 4.3%, 27.1%, and 30.3%, respectively. Compared with patients with PKD1 truncating mutations, patients with PKD1 in-frame insertion/deletion, PKD1 nontruncating, or PKD2 mutations have smaller htTKV and reduced risks (hazard ratio [95% confidence interval]) of ESRD (0.35 [0.14 to 0.91], 0.10 [0.05 to 0.18], and 0.03 [0.01 to 0.05], respectively) and death (0.31 [0.11 to 0.87], 0.20 [0.11 to 0.38], and 0.18 [0.11 to 0.31], respectively). Refined genotype-renal disease correlation coupled with targeted next generation sequencing of PKD1 and PKD2 may provide useful clinical prognostication for ADPKD.

HL156A is a novel AMP-activated protein kinase (AMPK) activator. We aimed to investigate the protective mechanism of HL156A against peritoneal fibrosis (PF) in in vivo and in vitro models. The rat PF model was induced by daily intraperitoneally injection of chlorhexidine (CHX) solution containing 0.1% CHX gluconate and 15% ethanol for 4 wk. The rats in the treatment group were treated with HL156A (1 mg·kg−1·day−1). Control rats were injected with vehicle alone. In vitro, cultured rat peritoneal mesothelial cells (RPMCs) were treated with either high glucose (HG; 50 mM), normal glucose (NG; 5 mM), NG+HL156A, or HG+HL156A. HL156A in supplemented rats ameliorated peritoneal calcification, cocoon formation, bowel obstruction, and PF. Immunohistochemistry showed reduced fibronectin accumulation in the peritoneum of HL156A-treated rats compared with those injected with CHX alone. HL156A treatment of RPMCs inhibited HG-induced myofibroblast transdifferentiation and markers of epithelial-mesenchymal transition (EMT). Moreover, HL156A ameliorated HG-induced transforming growth factor-β1, Smad3, Snail, and fibronectin expression in the RPMCs via AMPK upregulation. These results suggest that HL156A exhibits a protective effect in PF progression. Further research is warranted to seek the therapeutic potential of HL156A as an antifibrotic agent in peritoneal dialysis patients.

Mass effect from polycystic kidney and liver enlargement can result in significant clinical complications and symptoms in autosomal dominant polycystic kidney disease (ADPKD). In this single-center study, we examined the correlation of height-adjusted total liver volume (htTLV) and total kidney volume (htTKV) by CT imaging with hepatic complications (n = 461) and abdominal symptoms (n = 253) in patients with ADPKD. "Mass-effect" complications were assessed by review of medical records and abdominal symptoms, by a standardized research questionnaire. Overall, 91.8% of patients had 4 or more liver cysts on CT scans. Polycystic liver disease (PLD) was classified as none or mild (htTLV < 1,600 mL/m); moderate (1,600 = 3,200 mL/m). The prevalence of moderate and severe PLD in our patient cohort was 11.7% (n = 54/461) and 4.8%(n = 22/461), respectively, with a female predominance in both the moderate (61.1%) and severe (95.5%) PLD groups. Pressure-related complications such as leg edema (20.4%), ascites (16.6%), and hernia (3.6%) were common, and patients with moderate to severe PLD exhibited a 6-fold increased risk (compared to no or mild PLD) for these complications in multivariate analysis. Similarly, abdominal symptoms including back pain (58.8%), flank pain (53.1%), abdominal fullness (46.5%), and dyspnea/chest-discomfort (44.3%) were very common, and patients with moderate to severe PLD exhibited a 5-fold increased risk for these symptoms. Moderate to severe PLD is a common and clinically important problem in similar to 16% of patients with ADPKD who may benefit from referral to specialized centers for further management.

Autosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous and is caused by mutations in the PKD1 or PKD2 genes. ADPKD caused by PKD2 mutations is characterized by a longer survival and a later onset of end-stage renal disease than ADPKD caused by PKD1 mutations. PKD2 encodes a 2.9-kb messenger RNA and is derived from 15 exons. Two-dimensional gene scanning (TDGS) is more efficient in detecting mutations in genes such as PKD2 because it can scan the whole coding regions simultaneously. In order to determine the prevalence of Korean PKD2 patients, all the coding sequences of PKD2 were screened using TDGS and direct sequencing in 46 randomly selected ADPKD patients (group 1). Another 45 ADPKD patients (group 2), who were presumed to be PKD2 patients, were screened in order to identify the type of mutation in the Korean PKD2 patients. Eight novel different mutations and three known mutations in the PKD2 gene were detected in 17 patients: 6 patients (13.0%) in group 1 and 11 patients (24.4%) in group 2. Considering the sensitivity of TDGS, the prevalence of PKD2 in Korean population might be greater than 18.6%. Both known and novel mutations were identified by TDGS in Korean PKD2 patients. Overall, these results showed that TDGS might be useful for diagnosing PKD2.

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.

Autosomal dominant polycystic kidney disease (ADPKD) maps to chromosome 16p13.3 (PKD1) and to chromosome 4q21-23 (PKD2), with the likelihood of a third unmapped locus. The size and genomic complexity of the PKD1 gene make it impractical to detect mutations for prenatal diagnosis. Therefore, pedigree-based linkage analysis remains useful for diagnosis of ADPKD. Since, the complete genome sequences of chromosome 16p13.3 and 4q21-23 including PKD1 and PKD2, respectively, were reported very recently, in order to do more precise diagnosis of ADPKD, we tried to find microsatellite markers. We performed database searches of 2000 kb of genome sequence across the 16p13.3 and the 4q21-23. To determine the distribution of alleles and the degree of polymorphism of the microsatellites, genotyping experiments were performed on 48 Korean individuals. We found novel 14 microsatellite markers around ADPKD that are more polymorphic and closer to PKD1 or PKD2 than the known markers. The novel microsatellite markers were applied to diagnose ADPKD families. These novel microsatellite markers are not only useful for presymptomatic and prenatal diagnosis of ADPKD, but also applicable in the study of positional cloning, human evolution and tumor biology.

Purpose Evening administration of the conventional immediate-release (IR) formulation of simvastatin is recommended because of its short half-life (1.9 hours). In a healthy population, morning administration of a controlled-release (CR) formulation of simvastatin was shown to have equivalent lipid-lowering efficacy and a safety profile similar to that of evening doses of IR simvastatin. The present study aimed to verify noninferiority and to compare the safety of morning administration of CR simvastatin with that of evening administration of IR simvastatin in patients with chronic kidney disease (CKD) who have dyslipidemia. Methods The present study was a prospective, multicenter, double-blind, Phase IV trial with an active comparator. We randomly assigned 122 patients with CKD and dyslipidemia to 1 of 2 drug administration groups: morning administration of CR simvastatin 20 mg (test group) and evening administration of IR simvastatin 20 mg (control group). After 8 weeks, the treatment outcomes and adverse effects of the 2 treatments were compared. Findings The mean (SD) percentage of change in serum LDL-C at the end of treatment was –35.1% (15.7%) for the test group and –35.6% (14.6%) for the control group. The difference between the 2 groups was not significant ( P = 0.858). The 95% CI of the difference in the percentage of change of LDL-C between the test and control groups was –6.0 to 5.0. There was no difference in the percentage of change of total cholesterol (–24.3% [12.5%] vs –26.5% [12.0%], P = 0.317), triglyceride (–10.6% [35.1%] vs –12.4% [33.2%], P = 0.575) and HDL-C (10.2% [20.7%] vs 4.5% [11.4%], P = 0.064). Treatment-related adverse events were similar in both groups (10 events in the test group vs 8 events in the control group, P = 0.691). Implications The efficacy of morning administration of CR simvastatin was noninferior to evening administration of IR simvastatin in patients with CKD. Furthermore, the safety profile analysis showed no significant difference between the 2 treatments. Morning administration of CR simvastatin is expected to increase patient compliance and therefore better control of dyslipidemia in CKD patients.

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). 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. 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. No. NCT01630486 at http://www.clinicaltrials.gov .

A 51-year-old man was referred from on-cology department with incidental detection of unilateral multiple renal cysts on computed to-mography (CT) during evaluation of colon can-cer (Figure-1). Abdominal CT revealed enlarged right kidney with variable-sized round, well--marginated multiple cysts without capsule for-mation or solid content, while the left kidney was normal. Family history was negative for kidney disease. Ultrasound imaging of the parents, five adult siblings, one son and two daughters sho-wed normal kidneys. He received chemotherapy with 5-flurouracil plus leucovorin after laparos-copic right hemicolectomy for colon cancer. The relevant laboratory data were as follows: white blood cell count, 7000/mm3; hemoglobin level, 15.9 g/dL; platelet count, 174,000/mm3; blood urea nitrogen level, 15.5 mg/dL; creatinine level, 0.8 mg/dL and no proteinuria or hematuria. We did not introduce specific therapy for the unila-teral cyst and follow-up was made with magne-tic resonance image (MRI) six month after hemi-colectomy. The exam showed numerous cysts in the right kidney with no changes according to previous CT (Figure-2). This patient has unilateral renal cystic disease (URCD), a rare entity characterized by multiple cysts in one kidney or a portion of one

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) (r 2 = 0.153, P r 2 = 0.113, P Conclusions Urinary NAG/Cr may be a useful surrogate marker for renal function in ADPKD patients.

Poor renal function is associated with cardiovascular complications attributable to large-vessel diseases such as arterial calcification, heart failure, myocardial infarction, and cardiac mortality. The aim of this study was to evaluate the association between renal function and intracranial arterial stenosis (IAS). We analyzed the records of 283 stroke-free Korean adults (≥45 years of age) who underwent brain 3D time-of-flight magnetic resonance angiography as part of their voluntary health check. The presence of stenosis in the basilar artery and in the horizontal portion of the middle cerebral artery was defined as narrowing of the luminal diameter by 25% or more or occlusion on brain magnetic resonance angiography. We estimated the glomerular filtration rate using the Modification of Diet in Renal Disease equation. The subjects were 133 men and 150 women (mean age of 56 ± 7 years). One hundred sixty-six subjects (59 %) had IAS. The serum creatinine concentration in the highest quartile compared with the lowest quartile was associated with increased prevalence of IAS; the eGFR in the upper two quartiles compared with the lowest quartile were associated with decreased prevalence of IAS. The prevalence of subjects with a high eGFR decreased significantly with the severity of IAS. In conclusion, poor renal function is associated with the presence and the degree of IAS in stroke-free Korean adults.

The mortality and morbidity of end-stage renal failure patients remains high despite recent advances in pre-dialysis care. Previous studies suggesting a positive effect of pre-dialysis education were limited by unmatched comparisons between the recipients and non-recipients of education. The present study aimed to clarify the roles of the multidisciplinary pre-dialysis education (MPE) in chronic kidney disease patients. We performed a retrospective single centre study, enrolling 1218 consecutive pre-dialysis chronic kidney disease patients, between July 2007 and Feb 2008 and followed them up to 30 months. By using propensity score matching, we matched 149 recipient- and non-recipient pairs from 1218 patients. The incidences of renal replacement therapy, mortality, cardiovascular event and infection were compared between recipients and non-recipients of MPE. Renal replacement therapy was initiated in 62 and 64 patients in the recipients and non-recipients, respectively (P 0.05). The MPE reduced unplanned urgent dialysis (8.7% vs 24.2%, P 0.001) and shortened hospital days (2.16 vs 5.05 days/patient per year). MPE recipients had a better metabolic status at the time of initiating renal replacement therapy. Although no significant survival advantage from MPE was exhibited, MPE recipients had lower incidence of cardiovascular events (adjusted hazard ratio, 0.24; 95% confidence interval (CI), 0.08 to 0.78; P = 0.017), and a tendency toward a lower infection rate (adjusted hazard ratio, 0.44; 95% CI, 0.17 to 1.11; P = 0.083). MPE was associated with better clinical outcomes in terms of urgent dialysis, cardiovascular events and infection.

Vascular stiffness is associated with cardiovascular mortality in dialysis patients and related with vascular calcification and microvascular inflammation. The objective of this study is to compare predictability of two different vascular calcification scoring systems using plain radiographs in peritoneal dialysis (PD) patients.Vascular stiffness was represented by heart-to-femoral pulse wave velocity (hfPWV) in our 79 PD patients. Peripheral vascular calcification score (PVCS) and abdominal aortic calcification score (AACS) were measured from plain radiographs. Microvascular inflammation was represented by peritoneal protein clearance (PPC). Regression analysis and the receiver operating characteristic (ROC) curve analysis were used for analysis.The hfPWV revealed correlation with PVCS and AACS independently. In the ROC curve analysis, area under the curve (AUC) of PVC score was 0.7119 (P = 0.006), and AUC of AACS were 0.6960 (P = 0.011). After multiple linear regression analysis, PVCS remained as a predictor of vascular stiffness (R(2) = 0.579, β = 0.210, P = 0.038). The combination of PVCS and PPC exhibited a trend toward better predictability for vascular stiffness (AUC 0.7738, P = 0.001) than any of the two parameters alone.It is assumed that the PVCS system is more predictable for vascular stiffness in our study. Moreover, the combination of PVCS and PPC might be more useful as a screening test for vascular stiffness.

BACKGROUND: Complements play important roles in both rejection and ischemia-reperfusion injury after transplantation. Complement 5 (C5) is a pivotal complement, which initiates the assembly of the membrane attack complex, and mediates chemotaxis of various immune cells. We investigated the impacts of genetic variations in C5 and its receptor (C5aR) of both recipients and donors on renal allograft outcomes. METHODS: Seven single-nucleotide polymorphisms (SNPs) in C5 (rs12237774, rs2159776, rs17611, rs25681, rs2241004, rs10985126 and rs10818500) and one SNP (rs10404456) in the C5aR gene were genotyped in 191 recipient-donor pairs. The association of the polymorphisms with allograft outcomes was determined. RESULTS: Three C5 SNPs (rs2159776, rs17611 and rs25681) in recipients had a tendency toward a reduced glomerular filtration rate at 1 year after transplantation. There were four haplotypes in the H2 linkage disequilibrium block, which was formed by four SNPs (rs2159776, rs17611, rs25681 and rs2241004). The GGCG haplotype in both recipients and donors was associated with lower glomerular filtration rate at 1 year (60.9 ± 15.9 versus 66.4 ± 15.5 mL/min/1.73 m(2), P = 0.020; 60.6 ± 15.3 versus 66.2 ± 15.8 mL/min/1.73 m(2), P = 0.017). The association was sustained over 7 years after transplantation (P = 0.015 in recipients; P = 0.039 in donors). The presence of the GGCG haplotype in recipients was associated with poorer graft survival (logrank test, P = 0.024). However, C5 polymorphisms were not correlated with serum C5 level. C5aR polymorphism had no significant impact on the allograft outcomes. CONCLUSIONS: The GGCG haplotype of C5 in both recipients and donors was associated with lower renal allograft function.

BackgroundBetter glycemic control has been reported to slow the progression of nephropathy in predialysis diabetic patients. However, the relationship between glycemic control and residual renal function (RRF) in patients on peritoneal dialysis (PD) is uncertain.Methods89 incident diabetic patients on PD were recruited from 5 centers. We measured glomerular filtration rate (GFR) and hemoglobin A1c (HbA1c) within 2 months (baseline) after the start of PD and at 6 and 12 months. GFR was calculated as the average of renal creatinine and urea clearances. We analyzed whether mean HbA1c was associated with change in GFR (ΔGFR) over 1 year.ResultsDuring the first year of PD, ΔGFR was -1.7 ± 3.4 mL/min/1.73 m2and was not affected by mean HbA1c. Acute hemodialysis before starting PD and mean arterial diastolic pressure were related to the decline of GFR in a multivariate analysis.ConclusionGlycemic control was not associated with change in RRF in diabetic patients during the first year after starting PD.

The dentin sialophosphoprotein (DSPP) gene encodes the most abundant non-collagenous protein in tooth dentin and DSPP protein is cleaved into several segments including the highly phosphorylated dentin phosphoprotein (DPP). Mutations in the DSPP gene have been solely related to non-syndromic form of hereditary dentin defects. We recruited three Korean families with dentinogenesis imperfecta (DGI) type II and sequenced the exons and exon-intron boundaries of the DSPP gene based on the candidate gene approach. Direct sequencing of PCR products and allele-specific cloning of the highly repetitive exon 5 revealed novel single base pair (bp) deletional mutations (c.2688delT and c.3560delG) introducing hydrophobic amino acids in the hydrophilic repeat domain of the DPP coding region. All affected members of the three families showed exceptionally rapid pulp chambers obliteration, even before tooth eruption. Individuals with the c.3560delG mutation showed only mild, yellowish tooth discoloration, in contrast to the affected individuals from two families with c.2688delT mutation. We believe that these results will help us to understand the molecular pathogenesis of DGI type II as well as the normal process of dentin biomineralization.

An increase in aortic stiffness, as reflected by an increase in pulse wave velocity (PWV), is an important predictor of cardiovascular mortality in dialysis patients. Decreased serum concentration of calcification inhibitor, such as fetuin-A, is inversely related to mortality in haemodialysis patients. Our aim is to investigate the factors associated with aortic stiffness and its change over time in peritoneal dialysis (PD) patients.As a prospective observational study, we analysed 67 PD patients, aged 50 ± 14 years (mean ± SD) and with dialysis duration of 26 (5-58) months (median, interquartile range). At baseline, age, mean arterial pressure (MAP), left ventricular mass (LVM) index, diabetes, serum albumin, calcium (Ca), phosphorus (P) and intact parathyroid hormone (iPTH), uric acid, total bilirubin, high-sensitivity C-reactive protein (hsCRP), fetuin-A, and residual renal function were included in association analysis with aortic stiffness represented by heart-to-femoral PWV (hfPWV). We also evaluated simple vascular calcification score (SVCS) with plain radiograph of the pelvis and both hands. PWV was measured both at baseline and at 1 year. Change of aortic stiffness was determined by △PWV (difference between 1-year PWV and baseline PWV). Time-averaged concentrations were used to evaluate the relation between biologic markers and changes of aortic stiffness.hfPWV was 1022 ± 276 cm/s at baseline, and hfPWV determined at 1 year was 1069 ± 317 cm/s. Mean serum fetuin-A concentration was 0.34 ± 0.08 g/L. At baseline, aortic PWV positively correlated with age, smoking status, diabetes, MAP, total cholesterol and LDL cholesterol. On the other hand, aortic PWV inversely correlated with fetuin-A, log PTH, haemoglobin and albumin. In a multiple regression model, association of serum fetuin-A (β = -0.329, P = 0.003) with aortic PWV remained significant, along with age (β = 0.512, P0.001), MAP (β = 0.215, P = 0.047) and log PTH (β = -0.269, P = 0.025). At follow-up, △MAP (β = 0.500, P0.001) and time-averaged TG (aTG) (β = 0.259 P = 0.019) were determinants of △PWV.For our PD patients, serum fetuin-A was an independent determinant of aortic stiffness, as well as age, MAP and log PTH. Although 1 year is not sufficient to observe the change of aortic stiffness, some patients exhibited15% increase of PWV during this period. △MAP and aTG were factors affecting the change of PWV. Follow-up over a longer period is necessary to elucidate factors that determine changes of aortic stiffness over time from PD patients.

Fetuin-A is a negative acute-phase reactant and extraosseous calcification inhibitor. Decreased serum concentration of fetuin-A is independently related to all-cause and cardiovascular mortality in dialysis patients. Our aim is to investigate the association between the genetic polymorphism of alpha(2)-Heremans-Schmid-glycoprotein (AHSG) encoding fetuin-A and its serum concentration, vascular calcification, and aortic stiffness in peritoneal dialysis (PD) patients.A total of six single nucleotide polymorphisms (SNPs) in the AHSG gene were genotyped and evaluated for association with serum fetuin-A level, quantitative measures of vascular calcification and aortic stiffness represented by heart-to-femoral pulse wave velocity (hfPWV).Five SNPs in the AHSG gene were nominally associated with the serum fetuin-A level in our PD patients. In haplotype analyses, there were haplotypes positively (H1; AGCA, H2; CC) and inversely (H1; TTCG, H2; TT) related with the serum fetuin-A level. The serum fetuin-A level inversely and independently correlated with hfPWV. Moreover, the serum fetuin-A concentration was a determinant for the simple vascular calcification score (SVCS), which subsequently was associated with hfPWV.Our study showed an association between AHSG polymorphism and its serum concentration, and also revealed an association of the serum fetuin-A level with SVCS and aortic stiffness in PD patients.

Background Organ transplantation itself inevitably activates the innate immune system by toll-like receptors (TLRs), potentially leading to allograft rejection and graft failure. We evaluated the possible association between the TLR4/CD14 and TLR3 polymorphisms of donor-recipient pairs, and acute rejection after living donor kidney transplantation. Methods TLR4 -1607T/C (rs10759932), -2026A/G (rs1927914); CD14 -159C/T (rs2569190); and TLR3 rs3775290, rs3775291, and rs3775296 were genotyped using DNA samples from 216 donor-recipient pairs of adult living donor kidney transplantation between January 1996 and July 2006. Dual luciferase reporter assay was performed to determine the functional significance of promoter single-nucleotide polymorphisms (SNPs) of TLR4. Results Acute rejection occurred in 42 recipients (19.4%) of 216 adult transplant patients within 1 year. The genotype distributions of both recipient and donor TLR4 rs10759932 differed significantly between the control (no rejection) and acute rejection groups. For recipient rs10759932, the adjusted odds ratio for the TC+CC over TT genotype was 0.25 (95% confidence interval, 0.11-0.57; P =0.001). When the rs10759932 CC genotype was present in the recipient or donor, no episode of acute rejection occurred (Fisher's exact test, P =0.023). The presence of the rs10759932 C allele was associated with higher rejection-free survival rates (log-rank test, P =0.0053). However, there was no difference in transcriptional activity between wild-type and variant promoters of TLR4. In contrast to TLR4, SNPs of TLR3 or CD14 had no influence on acute rejection. Conclusion These findings suggest the importance of TLR4 in the pathogenesis of acute rejection in kidney transplantation.

To study the genetic effects of various inflammatory cytokines on peritoneal solute transport rate (PSTR) in incident Korean peritoneal dialysis (PD) patients.Case-control association study.132 patients with baseline peritoneal equilibration test within 1-3 months after starting PD were enrolled. We analyzed the influence of single nucleotide polymorphisms (SNPs) of interleukin-6 (IL-6; -572G/C, T15A), tumor necrosis factor-alpha (TNF-alpha; -1031C/T, -863C/A, -308G/A), and IL-10 (-1082A/G, -592A/C) on baseline PSTR. Clinical parameters such as age, gender, presence of diabetes mellitus, comorbidity, C-reactive protein, and residual renal function were also included as covariates.The T15A SNP of IL-6 (rs13306435) was associated with PSTR. Patients with TA genotype (n=18) had significantly lower D4/P creatinine (0.65+/-0.087 vs 0.73+/-0.110, p=0.0046) and higher D4/D0 glucose (0.39+/-0.174 vs 0.31+/-0.119, p=0.027) than patients with TT genotype (n=114). The log value of the dialysate appearance rate of IL-6 had a strong positive correlation with D4/P creatinine (r2=0.1294, p0.0001) and was significantly lower in the TA genotype than the TT genotype (201.7+/-14.42 vs 116.8+/-88.91 pg/minute, p=0.0358). By multiple logistic regression, TA genotype was negatively associated with a higher PSTR (high or high average; odds ratio 0.18; 95% confidence interval 0.048-0.666).In incident Korean PD patients, T15A polymorphism of IL-6 is associated with dialysate IL-6 concentration and baseline PSTR.

The pathogenic mechanisms of human autosomal dominant polycystic kidney disease (ADPKD) have been well known to include the mutational inactivation of PKD2. Although haploinsufficiency and loss of heterozygosity at the Pkd2 locus can cause cyst formation in mice, polycystin-2 is frequently expressed in the renal cyst of human ADPKD, raising the possibility that deregulated activation of PKD2 may be associated with the cystogenesis of human ADPKD. To determine whether increased PKD2 expression is physiologically pathogenic, we generated PKD2-overexpressing transgenic mice. These mice developed typical renal cysts and an increase of proliferation and apoptosis, which are reflective of the human ADPKD phenotype. These manifestations were first observed at six months, and progressed with age. In addition, we found that ERK activation was induced by PKD2 overexpression via B-Raf signaling, providing a possible molecular mechanism of cystogenesis. In PKD2 transgenic mice, B-Raf/MEK/ERK sequential signaling was up-regulated. Additionally, the transgenic human polycystin-2 partially rescues the lethality of Pkd2 knock-out mice and therefore demonstrates that the transgene generated a functional product. Functional strengthening or deregulated activation of PKD2 may be a direct cause of ADPKD. The present study provides evidence for an in vivo role of overexpressed PKD2 in cyst formation. This transgenic mouse model should provide new insights into the pathogenic mechanism of human ADPKD.

Background: Hemodialysis patients are prone to ischemic events potentially aggravated by hypoxia. The key player in adaptation to hypoxia is hypoxia-inducible factor-1 alpha (HIF-1α). Therefore, we investigated the association of HIF-1α polymorphisms with ischemia/hypoxia-related events in hemodialysis patients. Methods: Patients on maintenance hemodialysis were enrolled from 4 training hospitals in Korea. Seven single nucleotide polymorphisms (SNP) of HIF-1α were genotyped. The association of these SNP with hypoxia-related clinical outcomes (ischemic diseases and anemia) and cancer was analyzed. Results: A total of 376 patients participated in the study. No significant difference in genotype distribution was found between subjects with and without the hypoxia-related events. Three sets of linkage disequilibrium blocks were made for haplotype analyses (rs2783778 and rs7148720 in 5′ upstream region; rs7143164 and rs10873142; rs2301113, rs11549465 and rs2057482). Of these, the CT haplotype in the first set was associated with both acute myocardial infarction and frequent intradialytic hypotension (acute myocardial infarction: adjusted odds ratio = 0.15, 95% CI: 0.03–0.69; frequent intradialytic hypotension: adjusted odds ratio = 0.29, 95% CI: 0.12–0.72). Conclusion: Genetic polymorphisms of HIF-1α were associated with acute myocardial infarction and intradialytic hypotension in hemodialysis patients.

It is controversial whether comorbid status or systemic inflammation has an influence on the peritoneal solute transport rate (PSTR). Our aim is to elucidate whether baseline PSTR is associated with markers of systemic inflammation or degree of comorbidity in incident peritoneal dialysis (PD) patients.One hundred and ninety-five incident PD patients were prospectively included. Results of their baseline peritoneal equilibration test (PET) using 3.86% glucose PD fluid were analysed. Clinical and laboratory parameters of inflammation, comorbidity, nutritional status, dialysis adequacy and residual renal function (RRF) were assessed at the time of PET.Mean dialysate-to-plasma ratio for creatinine at 4 h (D/Pcr(4)) of our patients was 0.72 +/- 0.11. High-sensitivity C-reactive protein (hsCRP), serum interleukin-6 (IL-6) and serum albumin concentrations were closely interrelated to one another and these markers of systemic inflammation were also related to the Davies comorbidity score. No differences in age, sex ratio, body mass index, body surface area and presence of diabetes were found among four transport groups. RRF, total Kt/V, haemoglobin, nitrogen appearance and the Davies comorbidity score were not different either. High-sensitivity CRP, serum IL-6 and albumin concentrations were not associated with the baseline PSTR. By multiple linear regression analysis, only the serum albumin concentration measured at the time of PET (beta = -0.081 +/- 0.020, P0.001) remained significantly associated with D/Pcr(4).In our study with incident Korean PD patients, the baseline PSTR was not influenced by markers of systemic inflammation or comorbidity. For a subgroup of PD patients without serious comorbidity, other mechanisms of high baseline PSTR need to be elucidated.

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD). Genetic susceptibility plays an important role in the development and progression of diabetic nephropathy. Previous studies have revealed that polymorphisms in the SLC12A3 (solute carrier family 12 member [sodium/chloride] 3) gene, which encodes solute carrier family 12 member 3, might contribute to genetic susceptibility to diabetic nephropathy and essential hypertension. In this study, we examined whether the SLC12A3 gene locus is associated with ESRD resulting from diabetic nephropathy. We genotyped 11 common single nucleotide polymorphisms (SNPs) in the SLC12A3 gene in 177 patients with ESRD due to type 2 diabetes and 184 patients with diabetic retinopathy but with no signs of renal involvement. Three SNPs (g.34372G>A [Arg913Gln], g.39143G>A, and g.41727C>T) were found to be associated with ESRD due to diabetic nephropathy. These three SNPs were in complete linkage disequilibrium. Haplotype 4 in block 2 (18806C, 21822C, 34372A, 39143A, 39240T, 39375C, and 41727T) showed a significant association with ESRD due to type 2 diabetes (P = 0.0028). These results suggest that the SLC12A3 gene locus is associated with ESRD due to diabetic nephropathy.

Background Two genetic loci, PKD I and PKD2, have been identified as being responsible for ADPKD, and PKD1 is known to be associated with a poor prognosis. However, the presence of an intrafamilial study clinical diversity suggests that there are disease-modifying loci. Because the mechanism ofthe renal failure in ADPKD includes a cystic growth and tubulointerstitial atrophy and fibrosis, we studied the associations between 2 polymorphisms in the TGF-beta1 gene, which are known to be associated with chronic tubulointerstitial inflammation, and ADPKD progression in Korean patients. Patients and methods One hundred and twenty-five individuals who had ADPKD and 47 normal control subjects were genotyped by PCR-RFLP, the T869C (Leu10Pro) variant of TGF-beta gene leader sequence was discriminated with MspA1I and the G915C (Arg25Pro) variants with Bg1I. Statistical significances were determined using the Chi-square test. Results The distribution of the alleles for the TGF beta1 Leu10Pro polymorphism in ADPKD was: T 54%, C 46%, which was similar to the Korean (56: 44, p = 0.887) and Western controls (65: 35). In addition, no differences were found between the ESRD and the non-ESRD groups (p = 0.888) or the early hypertension and the normotension groups (p = 0.249). The distribution of alleles for the TGF beta1 Arg25Pro polymorphism showed only the GG type which was different from the Western population controls (G:C = 90:10, p = 0.000). Conclusions Our results suggest that the polymorphism at Arg25Pro of TGF-beta1 in the Korean population has an allele distribution different from that ofthe Western population and that the polymorphism at Leu10Pro of TGF-beta1 has no association with the renal progression in Korean ADPKD patients.

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.

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.

Cardiovascular disease (CVD) is the leading cause of death in renal allograft recipients with functioning graft. Our study aimed to determine the incidence and the risk factors of cardiovascular disease after renal transplantation in Korea. We retrospectively analyzed 430 adult recipients who underwent kidney transplantation between January 1997 and February 2007. CVD was defined as a composite outcome of ischemic heart disease, cerebrovascular accident and peripheral vascular disease. Mean age of recipients was 40.0±11.8 yr. Mean duration of follow-up was 72±39 months. The cumulative incidence of CVD after renal transplantation was 2.4% at 5 yr, 5.4% at 10 yr and 11.4% at 12 yr. Multivariate analysis revealed that recipient's age, diabetes mellitus and duration of dialysis before transplantation were associated with post-transplant CVD (hazard ratio 1.843 [95% CI, 1.005-3.381], 3.846 [95% CI, 1.025-14.432] and 3.394 [95% CI, 1.728-6.665] respectively). In conclusion, old age, duration of dialysis and diabetes mellitus are important risk factors for post-transplant CVD, although the incidence of post-renal transplant CVD is lower in Korea than that in western countries.

Macrophage infiltration has been observed in the renal biopsy specimens of diabetic nephropathy (DN), and hyperglycemic state stimulates the renal expression of RANTES (regulated upon activation, normal T-cell expressed and secreted) and MCP- 1 (monocyte chemoattractant protein-1). Upregulation of RANTES and MCP-1 with infiltrating macrophages may play a crucial role in the development and progression of DN. Genetic polymorphisms of RANTES and its receptors were reported to be independent risk factors for DN. We genotyped single nucleotide polymorphism (SNPs) in the MCP-1 G-2518A, CCR2 G46295A, RANTES C-28G and G-403A in 177 diabetic end-stage renal disease (ESRD) patients and 184 patients without renal involvement (controls) in order to investigate the effects of these SNPs on DN in Korean patients with type 2 DM. There were no differences in the frequencies of SNPs and the distribution of haplotypes of RANTES promoter SNPs between two groups. In conclusion, there were no associations of MCP-1, CCR2 and RANTES promoter SNPs with diabetic ESRD in Korean population. Prospective studies with clearly-defined, homogenous cohorts are needed to confirm the effect of these genetic polymorphisms on DN.

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