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Taiwan implemented national pay-for-performance programs for chronic kidney disease (CKD) care in 2006 and 2011; however, it is unknown whether this affected trends in maintenance dialysis. This study assessed the temporal trends in the incidence, prevalence, and mortality of individuals treated with maintenance dialysis from 2002-2016 in Taiwan.Follow-up study using Taiwan Renal Disease System Databases.Participants who received dialysis for ≥90 days.Age, sex, and calendar year.Incidence, prevalence of maintenance dialysis, or death, ascertained using the National Death Registry database.The estimated annual percentage change was assessed by a generalized linear model, and the association of the programs with changes in the incidence of maintenance dialysis was evaluated using an age-period-cohort model.A total of 144,258 incident cases with a follow-up of 346 million person-years were analyzed during the observed periods. The estimated annual percentage change of the expected crude incidence rate was slightly reduced by 0.41% (95% CI, -1.06 to 0.24) and was more obvious in women and patients aged greater than 70 years; whereas, it was significantly increased in those aged greater than 75 years. After disentangling age and cohort effects, the implementation of the care programs was associated with an overall net drift of -1.09% (95% CI, -1.65 to -0.52) per year and a significant linear reduction in the period rate ratio from 1.06 (95% CI, 1.02-1.09) in the years 2002-2006 to 0.95 (95% CI, 0.92-0.98) in 2012-2016, using years 2007-2011 as reference.The findings of the study may have limited inferences to other countries with different health care systems.The implementation of universal CKD care programs in Taiwan has significantly reduced the long-term trends in the incidence of maintenance dialysis; hence, devoting governmental resources to CKD care and prevention is advocated.

Diabetic kidney disease (DKD) is a microvascular complication that leads to kidney dysfunction and ESRD, but the underlying mechanisms remain unclear. Podocyte Wnt-pathway activation has been demonstrated to be a trigger mechanism for various proteinuric diseases. Notably, four-and-a-half LIM domains protein 2 (FHL2) is highly expressed in urogenital systems and has been implicated in Wnt/β-catenin signaling. Here, we used in vitro podocyte culture experiments and a streptozotocin-induced DKD model in FHL2 gene-knockout mice to determine the possible role of FHL2 in DKD and to clarify its association with the Wnt pathway. In human and mouse kidney tissues, FHL2 protein was abundantly expressed in podocytes but not in renal tubular cells. Treatment with high glucose or diabetes-related cytokines, including angiotensin II and TGF-β1, activated FHL2 protein and Wnt/β-catenin signaling in cultured podocytes. This activation also upregulated FHL2 expression and promoted FHL2 translocation from cytosol to nucleus. Genetic deletion of the FHL2 gene mitigated the podocyte dedifferentiation caused by activated Wnt/β-catenin signaling under Wnt-On, but not under Wnt-Off, conditions. Diabetic FHL2(+/+) mice developed markedly increased albuminuria and thickening of the glomerular basement membrane compared with nondiabetic FHL2(+/+) mice. However, FHL2 knockout significantly attenuated these DKD-induced changes. Furthermore, kidney samples from patients with diabetes had a higher degree of FHL2 podocyte nuclear translocation, which was positively associated with albuminuria and progressive renal function deterioration. Therefore, we conclude that FHL2 has both structural and functional protein-protein interactions with β-catenin in the podocyte nucleus and that FHL2 protein inhibition can mitigate Wnt/β-catenin-induced podocytopathy.

Catheter-related blood stream infection (CRBSI) is a major complication in hemodialysis patients. We assessed the efficacy of systemic daptomycin (DPT) plus DPT antibiotic lock therapy (DPT-ALT) for catheter salvage in patients with Gram-positive CRBSIs. This is a retrospective study of hemodialysis patients with tunneled and cuffed hemodialysis catheters. All patients were from a single institution in Taipei and received systemic DPT plus DPT-ALT for the treatment of Gram-positive CRBSI. Successful resolution of CRBSI was implemented. Resolution of fever within 48 hours, negative result of repeated blood cultures after resolution of fever, no clinical evidence of CRBSI relapse and no need for catheter removal were measured. Fifteen hemodialysis patients received DPT-ALT for CRBSI, nine with coagulase-negative Staphylococcus (CONS), two with methicillin-resistant Staphylococcus aureus (MRSA), three with methicillin-sensitive Staphylococcus aureus (MSSA) and one with polymicrobial infections. Systemic DPT plus DPT-ALT cured 11 patients (73.3%). Treatment failed in all three MRSA cases (two with MRSA and one with MRSA + Enterococcus faecalis). Retrospective design and small sample size were the limitations of this study. Systemic DPT plus DPT-ALT appears to be a promising treatment for CRBSI from CONS and MSSA, but not for MRSA CRBSI. Systemic DPT plus DPT-ALT should be considered for patients with CRBSIs caused by certain species.

Objectives There is a lack of consensus on the risk factors for hernia formation, and the impact on peritoneal dialysis (PD) survival has seldom been studied. Methods This was a population-based study and all collected data were retrieved from the National Health Insurance Research Database of Taiwan. Patients who commenced PD between January 1998 and December 2006 were screened for inclusion. Multiple logistic regression and Cox proportional hazards models were applied to estimate the predictors for hernia formation and determine the predictors of PD withdrawal. Results A total of 6,928 PD patients were enrolled and followed until December 2009, with 631 hernia events and 391 hernioplasties being registered in 530 patients (7.7%). The incidence rate was 0.04 hernias/patient/year. Longer PD duration (per 1 month increase, hazard ratio (HR) 1.019) and history of mitral valve prolapse (MVP) (HR 1.584) were independent risk factors for hernia formation during PD, and female gender (HR 0.617) was a protective factor. On the other hand, there were 4,468 PD withdrawals, with cumulative incidence rates of 41% at 1 year, 66% at 3 years, and 82% at 5 years. Independent determinants for cumulative PD withdrawal included hernia formation during PD (HR 1.154), age (per 1 year increase, HR 1.014), larger dialysate volume (per 1 liter increase, HR 0.496), female gender (HR 0.763), heart failure (HR 1.092), hypertension (HR 1.207), myocardial infarction (HR 1.292), chronic obstructive pulmonary disease (COPD) (HR 1.227), cerebrovascular accident (CVA) (HR 1.364), and history of MVP (HR 0.712) Conclusions Prolonged PD duration was a risk factor for hernia formation, and female gender was protective. Hernia formation during PD therapy may increase the risk of PD withdrawal.

BACKGROUND The process of vascular calcification has been associated with the canonical Wnt/β-catenin signalling pathway in cell cultures and animal studies. The relationship between circulating Wnt/β-catenin inhibitors and vascular calcification in dialysis patients is unknown. The aim of this study was to investigate the associations between serum dickkopf-1 (Dkk-1) and sclerostin, two circulating inhibitors of the Wnt/β-catenin signalling pathway, and the severity of aortic calcification (AoC) and cardiovascular outcomes in dialysis patients. METHODS This was a prospective observational cohort study. One hundred and twenty-five patients on maintenance haemodialysis participated in the study. Serum levels of Dkk-1 and sclerostin were measured. AoC scores were calculated from plain films of both posterior-anterior and lateral views. The patients were followed up for 2 years or until death or withdrawal. RESULTS The circulating sclerostin level was inversely associated with the severity of AoC (P = 0.035) and indicators of the bone turnover rate including serum alkaline phosphatase (ALP) (r = -0.235, P = 0.008) and intact parathyroid hormone (r = -0.523, P < 0.001). Furthermore, Cox regression analysis indicated that the patients with high circulating sclerostin levels were less likely to experience future cardiovascular events [1 pmol/L sclerostin increase, hazard ratio 0.982 (95% CI, 0.967-0.996), P = 0.015] after adjusting for a propensity score. In contrast, serum Dkk-1 was not associated with AoC and clinical outcomes. CONCLUSIONS In long-term haemodialysis patients, circulating sclerostin but not Dkk-1 is inversely associated with AoCs and future cardiovascular events. Our findings suggest that sclerostin, as a bone-related protein, might act as a communicator between uraemic bone and vasculature.

Objective Acute kidney injury is a common and serious problem after cardiac surgery. Postoperative acute kidney injury is independently associated with in-hospital mortality and long-term morbidity, even after adjustment for comorbid diseases. Chronic kidney disease has been recognized as a strong risk factor of acute kidney injury after cardiac surgery. The association between proteinuria and postcardiotomy acute kidney injury in patients with preserved glomerular filtration rate remains uncertain. Methods Patients with an estimated glomerular filtration rate greater than 60 mL/min/1.73 m 2 who underwent cardiac surgery between January 2003 and December 2007 in a tertiary medical center were retrospectively analyzed. Dipstick urinalysis was performed before surgery. Proteinuria was categorized into negative, trace, 1+, 2+, or 3+. Postoperative acute kidney injury was defined by the Acute Kidney Injury Network criteria. Multinomial logistic regression was used to clarify whether proteinuria is an independent risk factor of postoperative acute kidney injury. Results A total of 1246 patients were included in this study, with a mean estimated glomerular filtration rate of 80 ± 13 mL/min/1.73 m 2 . Proteinuria was present in 290 patients (23.4%). Postoperative acute kidney injury developed in 434 patients (34.8%), and 36 patients (2.9%) required renal replacement therapy. Proteinuria was independently associated with all stages of postcardiotomy acute kidney injury and dialysis-requiring acute kidney injury. The crude risk of acute kidney injury was greater in patients with a higher grade of proteinuria. In subgroup analysis for gender, diabetes, and surgical type, preoperative proteinuria remains a strong risk factor of acute kidney injury after cardiac surgery. Conclusions Urine analysis is usually neglected before cardiac surgery despite the fact that proteinuria is the earliest manifestation of kidney dysfunction. In the current study, we show that urine protein is strongly and independently associated with postoperative acute kidney injury in subjects with preserved estimated glomerular filtration rate. These data suggest that such a relatively simple and clinically easy to use tool as a urinary dipstick may be useful to identify patients at high risk of acute kidney injury before cardiac surgery.

Background/Aims: Hyperparathyroidism (HPT) is a common complication of chronic kidney disease and contributes to hypertension and cardiovascular risks. Successful kidney transplantation corrects abnormal mineral metabolism, but persistent HPT is still observed in up to 25% of patients one year after transplantation despite renal function improvement. The purpose of this study was to examine the long-term effects of parathyroidectomy (PTX) on blood pressure (BP) and graft function in patients with persistent post-transplant HPT. Methods: This is a retrospective study of renal allograft recipients at a single institute. Records from all the patients who received kidney transplantation at the Taipei Veterans General Hospital between 2004 and 2012 were reviewed and enrolled 19 patients who underwent PTX for persistent post-transplant HPT. Preoperative and postoperative clinical and biochemical data were compared. Matched controls (n = 19) in the corresponding time span were enrolled for graft function comparisons. Results: The mean systolic BP (127.7 ± 14.3 to 119.5 ± 12.7 mmHg, p = 0.028, 1 year after PTX; 127.7 ± 14.3 to 117 ± 12.4 mmHg, p = 0.007, 2 years after PTX) and pulse pressure (PP) (51.3 ± 10.7 to 44.3 ± 11.6, p = 0.019 1 year after PTX; 51.3 ± 10.7 to 44.9 ± 12.5 mmHg, p = 0.028, 2 years after PTX) reduced significantly at 1 year and 2 years of follow-up. However, no significant change of diastolic BP was observed. The improvement of SBP, DBP and PP was not correlated with the reduction of serum calcium level 1 year after PTX. The estimated glomerular filtration rate decreased significantly from 74.0 ± 20.5 mL/min/1.73m2 preoperatively to 68.2 ± 24.8 mL/min/1.73 m2 12 months after PTX but recovered at 15 months and lasted to 2 years after PTX. The all-cause hospitalization rate 1 year after PTX tended to be higher than that 1 year before PTX (105.3 versus 47.4 per 100 patient-years; RR, 2.22; 95 % CI: 0.97-5.54), but there was no significant difference between them. Conclusions: Our study demonstrated systolic BP and PP reduced 2 years after PTX and there was no significant difference between the peri-operative all-cause hospitalization rates. In addition, kidney allograft function impaired temporarily 12 months after PTX, but recovered 15 months after PTX.

Diabetic nephropathy is characterized by excessive deposition of extracellular matrix protein and disruption of the glomerular filtration barrier. Matrix metalloproteinases (MMPs) affect the breakdown and turnover of extracellular matrix protein, suggesting that altered expression of MMPs may contribute to diabetic nephropathy. Here we used an MMP-9 gene knockout mouse model, with in vitro experiments and clinical samples, to determine the possible role of MMP-9 in diabetic nephropathy. After 6 months of streptozotocin-induced diabetes, mice developed markedly increased albuminuria, glomerular and kidney hypertrophy, and thickening of the glomerular basement membrane. Gelatin zymographic analysis and western blotting showed that there was enhanced MMP-9 protein production and activity in the glomeruli. However, MMP-9 knockout in diabetic mice significantly attenuated these nephropathy changes. In cultured podocytes, various cytokines related to diabetic nephropathy including TGF-β1, TNF-α, and VEGF stimulated MMP-9 secretion. Overexpression of endogenous MMP-9 induced podocyte dedifferentiation. MMP-9 also interrupted podocyte cell integrity, promoted podocyte monolayer permeability to albumin, and extracellular matrix protein synthesis. In diabetic patients, the upregulation of urinary MMP-9 concentrations occurred earlier than the onset of microalbuminuria. Thus, MMP-9 seems to play a role in the development of diabetic nephropathy.Kidney International advance online publication, 26 March 2014; doi:10.1038/ki.2014.67.

Malfunction of the arteriovenous fistula (AVF) is an important cause of morbidity and hospitalization in hemodialysis (HD) patients. The aim of this study is to evaluate the effect of far infrared therapy on the maturation and patency of newly created AVFs in patients with chronic kidney disease stage 4 or 5.Randomized controlled study.Patients with estimated glomerular filtration rate of 5-20 mL/min/1.73 m².40 minutes of far infrared therapy 3 times weekly for a year.The primary outcome is the rate of AVF malfunction within 12 months, with malfunction defined as either: (1) thrombosis without thrill for AVFs not undergoing HD or (2) receiving any type of interventional procedure due to a lower Kt/V (1.2) for patients undergoing HD. Secondary outcomes include: (1) cumulative primary unassisted AVF patency, defined as time from creation of the AVF to the first episode of AVF malfunction; (2) physiologic maturation of the AVF by the definition of AVF access blood flow (Qa) ≥500 mL/min and AVF diameter ≥4 mm at 3 months; and (3) clinical maturation of the AVF suitable for HD at 1 year.AVF Qa was measured by Doppler ultrasonography at 2 days and 1, 2, 3, and 12 months.We enrolled 122 patients who were randomly allocated to the intervention (n = 60) and control (n = 62) groups. In comparison to controls, patients in the intervention group had higher Qa values at 1, 2, 3, and 12 months; a higher rate of physiologic maturation (90% vs 76%; P = 0.04) at 3 months; and a lower rate of AVF malfunction (12% vs 29%; P = 0.02) but higher rates of AVF cumulative unassisted patency (87% vs 70%; P = 0.01) and clinical maturation (82% vs 60%; P = 0.008) within 12 months.This is a single-center nonblinded study.Far infrared therapy improves the access flow, maturation, and patency of newly created AVFs in patients with chronic kidney disease stages 4 and 5.

Background: Secondary hyperparathyroidism is associated with vascular calcification and arterial stiffness in patients with end-stage renal disease. The aim of this study was to analyze the frequency of intradialytic hypotension (IDH) and cardiovascular function before and after parathyroidectomy (PTX) in maintenance hemodialysis patients. Methods: We compared predialytic and intradialytic blood pressure, left and right ventricular ejection fraction (LVEF and RVEF), and cardiothoracic ratio 1 month before PTX, and 6 and 12 months after PTX. IDH was defined as a decrease in systolic blood pressure ≥ 20 mmHg or a decrease in mean arterial pressure ≥ 10 mmHg. Results: At the time of PTX, the mean age of the patients was 57.4 ± 12.0 years, and the mean dialysis vintage was 12.2 ± 5.8 years. At baseline, 6 months, and 12 months after PTX, the average numbers of sessions disturbed by IDH during 13 dialysis sessions (1 month) were 6.4, 3.9 (p < 0.016 vs. baseline), and 4.0 sessions (p < 0.037 vs. baseline, p = 0.801 vs. 6 months), respectively. LVEF and RVEF were improved significantly after PTX. Furthermore, volume status was also improved, as evidenced by the significantly greater ultrafiltration volume and reduced cardiothoracic ratio. Conclusions: Hemodialysis patients with severe secondary hyperparathyroidism are more likely to achieve normotensive and euvolemic status after PTX, probably through improved heart function and reduced IDH episodes.

Background/Aims: Contrast-induced nephropathy (CIN) is the third most common cause of hospital-acquired acute renal failure. However, the pathogenesis of CIN remains unclear. This study evaluated the role of anti-inflammatory cytokine interleukin-10 (IL-10) and pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) gene polymorphisms as CIN susceptibility markers after percutaneous coronary intervention (PCI). Methods: Four IL-10 tag SNPs (rs1554286, rs3021094, rs3790622, rs1800896) and three TNF-α tag SNPs (rs1799964, rs1800630, rs1800629) were analyzed by MALDI-TOF mass spectrometry in 53 CIN patients and 455 control subjects. Serum IL-10 and TNF-α were detected using ELISA. Results: When compared to controls, the CIN patients showed increased frequencies of CC (rs1554286) and AG+GG (rs1800896) genotypes in IL-10 and GA+AA (rs1800629) genotype in TNF-α (OR = 2.24 (1.13–4.44), p = 0.018; OR = 2.61 (1.30–5.26), p = 0.005, and OR = 2.11 (1.08–4.09), p = 0.025, respectively). Baseline serum IL-10 levels in CIN patients were significantly lower (1.02 ± 1.14 vs. 2.78 ± 4.73 pg/ml, p = 0.008). Patients with CIN had a higher rate of decline in renal function than those without CIN (0.89 ± 1.67 vs. 0.30 ± 0.95 ml/min/1.73 m2 per month, p = 0.002). Significantly higher rates of decline in creatinine clearance were noted in patients with TNF-α (rs1800629) GA+AA than GG genotype (0.88 ± 1.83 vs. 0.36 ± 0.70, p = 0.03), and with IL-10 (rs1800896) AG+GG than AA genotype (1.28 ± 2.14 vs. 0.33 ± 0.90, p < 0.001). Conclusions: Gene polymorphisms of IL-10 and TNF-α are associated with CIN risk and long-term renal outcome after PCI. More prospective studies are needed to confirm our results.

The life qualities of end-stage renal disease (ESRD) patients rely largely on adequate dialysis, and a well-functioning vascular access is indispensable for high quality hemodialysis. Despite the advancement of surgical skills and the optimal maintenance of arteriovenous fistula (AVF), malfunction of AVF is still frequently encountered and has great impact on the life of ESRD patients. Several medical, mechanical and genetic prognostic factors are documented to affect the patency of AVF and arteriovenous graft (AVG). Heme oxygenase-1 (HO-1) is one of the genetic factors reported to play a role in cardiovascular disease and the patency of vascular access. Far infrared (FIR), a novel therapeutic modality, can not only conduct heat energy to AVF but also stimulate the non-thermal reactions mediated by HO-1. The use of FIR therapy significantly enhances the primary patency rate and maturation of AVF with fewer unfavorable adverse effects, and also achieves higher post-angioplasty patency rate for AVG. The only limitation in proving the effectiveness of FIR therapy in enhancing patency of AVF is that all the studies were conducted in Chinese people in Taiwan and thus, there is a lack of evidence and experience in people of other ethnicities.

Background: Polycystic kidney disease (PCKD) is one of the most common inherited disorders in end-stage renal disease patients. It is generally thought that the survival of PCKD patients undergoing dialysis sur- passes that of general dialysis patients, but the cause of this improved survival is not clear. Methods: Using Taiwan's national health insurance claims data, we performed a longitudinal cohort study to investigate the survival and impact of comorbidi- ties on mortality in dialysis patients with and without PCKD. We excluded patients without diabetes mellitus (DM) in a further analysis. A Cox proportional hazards model was used to identify the risk factors for all- cause mortality. The Kaplan-Meier method was used to describe overall patient survival. Results: Five hundred and one (2.25%) of 22,298 non- diabetic incident dialysis patients had PCKD. We found no significant difference in survival rates be- tween those with and without PCKD. Being male, being over 65 years old and having congestive heart failure or cerebrovascular accident were each found to be independent predictors of mortality in the PCKD dialysis patients. Conclusions: Taiwan has a lower incidence rate of PCKD than Western countries. In Taiwan, there is little difference in the long-term survival between dialysis patients with and without PCKD.

Nitric oxide (NO) is a pivotal vasoactive substance modulating arteriovenous fistula (AVF) patency for hemodialysis (HD). Since genetic background could be the predicting factor of AVF malfunction, we aimed to investigate whether the NO-related genotype polymorphisms determine AVF survival rates.This is a retrospective, observational, multi-center study involving eight HD units in Taiwan, enrolled 580 patients initiating maintenance HD via AVFs. Genotype polymorphisms of NO-biosynthesis regulating enzymes (DDAH-1, DDAH-2, eNOS and PRMT1) were compared between HD patients with (n = 161) and without (n = 419) history of AVF malfunction. Subgroup analyses by gender were performed to evaluate the genetic effect in difference sexes.In overall population, statistically significant associations were not found between AVF malfunction and the genetic polymorphisms. In the male subgroup (n = 313), a single nucleotide polymorphism (SNP) of PRMT1, rs10415880 (IVS9-193 A/G), showed a significant association with AVF malfunction. Male patients with AA/AG genotype had inferior AVF outcomes compared to GG genotype, regarding primary patency (70.6% vs. 40.9%, p = 0.001), assisted primary patency (81.0% vs. 58.4%, p 0.001) and secondary patency (83.7% vs. 63.3%, p 0.001) at a 5-year observation period. From multivariate Cox regression model, the AA/AG genotypes of PRMT1 were an independent risk factor for AVF malfunction in men (HR: 4.539, 95% CI 2.015-10.223; p 0.001). However, such associations were not found in women.rs10415880, the SNP of PRMT1 could be a novel genetic marker associated with AVF malfunction risk in male HD patients. Those with AA and AG genotypes of rs10415880 may predict a poorer long-term patency of AVF.

Aim: Overseas kidney transplantation has often been reported to have unsatisfactory outcomes. This study aims to compare post-transplantation outcomes between overseas and domestic kidney transplant (KT) recipients in Taiwan. Methods: The Taiwanese National Health Insurance Research Database was used to identify 310 domestic and 643 overseas KT recipients, who survived for longer than 1 month after the transplantation, in a cohort of 45 453 chronic haemodialysis patients in 1997–2002. Cox proportional hazards models were used to assess risks of mortality and graft failure. Results: The 1, 3 and 5 year survival rates for domestic KT recipients were 96.5%, 93.3% and 91.6%, respectively, while those for overseas KT recipients were 94.9%, 87.9% and 77.1%, respectively (P = 0.015). For the overseas group, those who received a KT before 2001 had significantly higher hazard ratios of mortality and graft failure (2.85 and 1.71, respectively). However, for those receiving a KT in 2001–2002, no significant outcome difference could be found between overseas and domestic recipients. Conclusion: The risk disparity between overseas and domestic KT recipients is mainly attributable to when the transplantation was performed. In attempting to dissuade potential recipients from organ trafficking, merely emphasizing the previously acknowledged poor outcomes no longer suffices as a valid reason.

Elevated levels of serum pancreatic enzymes are frequently observed in hemodialysis (HD) patients. The complex hemodynamic, biochemical, and physiological alterations in uremia were speculated to cause excessive release of pancreatic enzymes beyond decreased renal clearance. However, hemodynamic factors are seldom explored in this aspect. We performed the study to evaluate the association between intradialytic hemodynamic change and elevated serum pancreatic amylase (SPA). Eighty-three prevalent HD patients without any clinical evidence of acute pancreatitis underwent pre-HD and post-HD blood sampling for serum pancreatic enzyme levels. Demographic, biochemical, and hematological data were collected from patient record review. Hemodialysis information including intradialytic blood pressure changes and ultrafiltration (UF) amount were collected and averaged for 1 month before the blood sampling day. Patients with elevated SPA during the HD session had greater mean systolic blood pressure and mean arterial pressure reduction, greater UF volume, greater pre-HD blood urea nitrogen and serum creatinine, higher serum phosphorus, lower pre-HD serum total CO2, and lower left ventricle ejection fraction (LVEF). Using multivariate linear and logistic regression analysis, the independent predictors of elevated SPA were determined to be mean arterial pressure reduction during HD, mean UF amount, pre-HD serum total CO2, and LVEF. Greater blood pressure reduction during HD, greater UF volume, lower pre-HD serum total CO2, and lower LVEF were significantly associated with elevated SPA during HD. This suggests that hemodynamic factors contribute to elevated serum pancreatic enzymes in HD patients.

Dual renin angiotensin system (RAS) blockade using angiotensin-receptor blockers (ARBs) in combination with angiotensin converting enzyme inhibitors (ACEIs) is reported to improve proteinuria in both diabetic and non-diabetic patients. However, its renoprotective effect and safety remain uncertain in patients with advanced chronic kidney disease (CKD). From January 1, 2000 through June 30, 2009, we enrolled 14,117 pre-dialytic stage 5 CKD patients with serum creatinine >6mg/dL and hematocrit

Background The pathological recognition of secondary membranous nephropathy (MN) is sometimes difficult, especially in those showing primary idiopathic MN-like histomorphology. The ultrastructural finding of tubuloreticular inclusions (TRIs) in MN always evokes suspicion of their association with underlying diseases such as viral infections and autoimmune diseases. However, it is not clear whether some other underlying diseases are associated with TRI expression in MN. Since treatment of the underlying diseases is the primary consideration for the management of secondary MN, it is important to make out the clinical significance of TRI expression in MN. Methods Excluding the patients fully qualified for systemic lupus erythematosus (SLE) diagnostic criteria, we recruited 36 cases having a renal biopsy featured with histopathology of primary idiopathic MN but ultrastructural appearance of TRIs in glomerular endothelial cells (GECs). We investigated their clinical and pathological profiles and focused on the potential connections with the underlying diseases and treatment outcomes. Results One-third of our cases showed no identifiable underlying aetiology. Other underlying disease groups included autoimmune disease (25%), hepatitis (14.7%), potential Helicobacter pylori infection (13%), diabetes (5.6%) and lymphoma (5.6%). Pathologically, patients in the autoimmune group tended to have more heterogeneous membranous deposits with frequent mesangial and subendothelial deposits. While all patients of the autoimmune group presented complement C1q in glomeruli, more than two-thirds of the patients in others groups were negative for C1q. Clinically, the patients in autoimmune and hepatitis groups were younger in age and had less remission of proteinuria following treatment, while the other groups of patients achieved partial or complete remission more frequently. Conclusion The underlying diseases of our patients were consistent with the major disease categories that have been frequently linked to secondary MN. The HP group was more akin to undefined groups regarding their pathological and clinical profiles. Since the MN in the undefined group might be the only renal manifestation antedating other clinical presentations of the corresponding underlying disease, a long-term follow-up and meticulous search for aetiological factors are required to validate this assumption.

Background/Aims: Pentoxifylline (PTX) has been shown to inhibit renal inflammation in a rat model of crescentic glomerulonephritis. The present study investigated the role of PTX in renal fibrosis in rats with crescentic glomerulonephritis. Methods: A rat model of accelerated anti-glomerular basement membrane glomerulonephritis was induced and treated with PTX or vehicle control for 3, 7, 14 and 28 days. The therapeutic effect and mechanism of PTX on renal fibrosis were examined by Northern blot and immunohistochemistry. Results: Diseased rats treated with vehicle control developed a severe crescentic glomerulonephritis with progressive renal fibrosis identified by a marked accumulation of α-SMA+ myofibroblasts and collagen matrix. This was associated with tubular epithelial-myofibroblast transition as evident by de novo expression of α-SMA and a loss of E-cadherin on damaged tubular epithelial cells. Further studies revealed that severe renal fibrosis was associated with upregulation of renal TGF-β1 and activation of TGF-β/Smad signaling, which was blocked by treatment with PTX. Conclusions: PTX may be an anti-fibrosis agent capable of inhibiting renal fibrosis in a rat model of crescentic glomerulonephritis. Blockade of TGF-β1 expression and Smad2/3 activation may be a mechanism by which PTX inhibits renal fibrosis.

Background Incident and prevalent (I&P) rates in dialysis end-stage renal disease (ESRD) patients in Taiwan increased rapidly following the launch of National Health Insurance (NHI) in 1995. Our aim was to explore the impact of NHI on the status and trends of ESRD epidemiology in Taiwan. Methods This study was conducted using retrospective cohort analysis of data collected from the Taiwan national dialysis registry. Results From 1990 to 2001, I&P rates of ESRD patients increased 2.6 times from 126 to 331 per million populations (pmp) and 3.46 times from 382 to 1322 pmp, respectively. Increasing ESRD was seen in patients who were middle-aged, elderly and who had diabetic nephropathy as their primary renal disease. The mean age of I&P patients increased by 7.2 years and 7.1 years, respectively. All of these parameters increased markedly in 1995, the year of NHI implementation. First-year mortality decreased to 7.8 per 1000 patient-months in 1994, and then increased to 18.0 in 2001. The cumulative survival rate of the elderly subgroup (age >65) in the incident 1990-1994 cohort was greater than in the 1995-1999 cohort. These data indicated that NHI implementation significantly influenced the inflow and the mortality of ESRD patients. Conclusion In addition to presenting ESRD epidemiology in Taiwan, this study demonstrated that NHI implementation stimulated the growth of treated ESRD populations. Preventive plans mounted against chronic kidney diseases will be essential to reduce the growth of ESRD patient numbers and consequent economic burdens.

Taiwan has the world's highest incidence and second highest prevalence of end-stage renal disease (ESRD), particularly in older age groups. However, the transition from chronic kidney disease (CKD) to death or ESRD remains unclear. This study aimed to investigate the impact of late-stage CKD on all-cause and cause-specific mortality by identifying the CKD population.This was an observational cohort study (n = 35 529), mean age 75.7 years (SD = 5.3), of participants in the Elderly Health Examination Program (EHEP) in Kaohsiung City, Taiwan, between 2002 and 2004. Estimated glomerular filtration rate (eGFR) was calculated by the simplified modified diet in renal disease equation. Proportional hazard ratios (HR) of mortality associated with late-stage CKD were assessed by Cox regression.The crude prevalence rate of CKD stages 3-5 was 39.4%; 1840 participants (5.18%) died within 2-year follow-up, a mortality rate of 20.3 per 1000 person-years overall and 16.4 per 1000 person-years in the reference group. Higher HR for all-cause and cause-specific mortality were found in the groups with decreased eGFR. Compared with the reference group (eGFR60 mL/min/1.73 m(2)), adjusted HR for all-cause mortality were 1.5, 2.1 and 2.6 for groups with eGFR 30-44, 15-29 and15 mL/min/ 1.73 m(2), respectively (P0.001). Higher HR of mortality due to cardiovascular or renal diseases were also significantly associated with decreased eGFR (P0.05).Late-stage CKD is a significant risk factor for mortality, especially due to cardiovascular and renal diseases, in elderly Taiwanese. Given the higher prevalence rate of late-stage CKD in the study area, CKD patient mortality was relatively lower, which might reflect underestimation of renal function for patients at early stages of CKD, or partly explain the high ESRD population.

Vascular access malfunction, usually presenting with an inadequate access flow (Qa), is the leading cause of morbidity and hospitalization in hemodialysis (HD) patients. Many methods of thermal therapy have been tried for improving Qa but with limited effects. This randomized trial was designed to evaluate the effect of far-infrared (FIR) therapy on access flow and patency of the native arteriovenous fistula (AVF). A total of 145 HD patients were enrolled with 73 in the control group and 72 in the FIR group. A WS TY101 FIR emitter was used for 40 min, and hemodynamic parameters were measured by the Transonic HD(02) monitor during HD. The Qa(1)/Qa(2) and Qa(3)/Qa(4) were defined as the Qa measured at the beginning/at 40 min later in the HD session before the initiation and at the end of the study, respectively. The incremental change of Qa in the single HD session with FIR therapy was significantly higher than that without FIR therapy (13.2 +/- 114.7 versus -33.4 +/- 132.3 ml/min; P = 0.021). In comparison with control subjects, patients who received FIR therapy for 1 yr had (1) a lower incidence (12.5 versus 30.1%; P < 0.01) and relative incidence (one episode per 67.7 versus one episode per 26.7 patient-months; P = 0.03) of AVF malfunction; (2) higher values of the following parameters, including Delta(Qa(4) - Qa(3)) (36.2 +/- 82.4 versus -12.7 +/- 153.6 ml/min; P = 0.027), Delta(Qa(3) - Qa(1)) (36.3 +/- 166.2 versus -51.7 +/- 283.1 ml/min; P = 0.035), Delta(Qa(4) - Qa(2)) (99.2 +/- 144.4 versus -47.5 +/- 244.5 ml/min; P < 0.001), and Delta(Qa(4) - Qa(2)) - Delta(Qa(3) - Qa(1)) (62.9 +/- 111.6 versus 4.1 +/- 184.5 ml/min; P = 0.032); and (3) a better unassisted patency of AVF (85.9 versus 67.6%; P < 0.01). In conclusion, FIR therapy, a noninvasive and convenient therapeutic modality, can improve Qa and survival of the AVF in HD patients through both its thermal and its nonthermal effects.

Background: The burden of chronic kidney disease (CKD) is a global challenge. Empirical evidence of low CKD awareness rates in developed countries speaks for an urgent need to strengthen strategies for CKD identification and prevention. The aim of this study is to estimate the awareness rate of CKD in Taiwan to promote early detection of CKD in this country. Methods: Data from a nationally representative survey were used for analysis. The study included 6,001 subjects. The simplified Modification of Diet in Renal Disease equation was used to define glomerular filtration rate (GFR) and CKD stages according to criteria of the US National Kidney Foundation. Descriptive methods were used to analyze data. Results: The prevalence of CKD stages 3 to 5 in Taiwan is 6.9% (95% confidence interval, 4.4 to 9.4). Awareness rates for CKD in Taiwan are low: 8.0% for individuals with stage 3, 25.0% for those with stage 4, and 71.4% for those with stage 5. Awareness rate is related closely to serum creatinine level: those with creatinine levels greater than 1.6 mg/dL (>141 μmol/L) are more likely to be informed of having a kidney disease. Conclusion: The high prevalence and low awareness of CKD in Taiwan explicitly show the need to advocate more strongly for CKD prevention and education for both physicians and the populace. Establishment of a mandated automatic GFR reporting system may be the first priority we need to accomplish in Taiwan to improve kidney well-being.

Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in heme degradation, producing carbon monoxide (CO), which carries potent antiproliferative and anti-inflammatory effects in the vascular walls. Transcription of the HO-1 gene is regulated by the length polymorphism of dinucleotide guanosine thymine repeat (GT)(n) in the promoter region, which was measured in this study to determine its association with arteriovenous fistula (AVF) failure in Chinese hemodialysis (HD) patients in Taiwan. L allele means (GT)(n)or=30 and S allele means (GT)n30. Therefore, there are two L alleles for L/L genotype, one L and one S allele for L/S genotype, and two S alleles for S/S genotype. Among the 603 HD patients who were enrolled in this study, 178 patients had history of AVF failure, while 425 patients did not. Significant associations were found between AVF failure and the following factors (hazard ratio): longer HD duration (1.004 month), lower pump flow (0.993 ml/min), higher dynamic venous pressure (1.010 mmHg), location of AVF on the right side (1.587 vs left side) and upper arm (2.242 vs forearm), and L/L and L/S genotypes of HO-1 (2.040 vs S/S genotype). The proportion of AVF failure increased from 20.3% in S/S genotype and 31.0% in L/S genotype to 35.4% in L/L genotype (P=0.011). Relative incidences were 1/87.6 (1 episode per 87.6 patient-months), 1/129, and 1/224.9 for HD patients with L/L, L/S, and S/S genotypes, respectively (P0.002). The unassisted patency of AVF at 5 years decreased significantly from 83.8% (124/148) to 75.1% (223/297) and 69% (109/158) in S/S, L/S, and L/L genotypes, respectively (P0.0001). In comparison with HD patients with S/S genotype, those with L/L genotype had a higher prevalence of coronary artery disease (29.1 vs 14.2%; P=0.005). A longer length polymorphism with (GT)(n)or=30 in the HO-1 gene was associated with a higher frequency of access failure and a poorer patency of AVF in HD patients. The longer GT repeat in the HO-1 promoter might inhibit gene transcription, and consequently offset the CO-mediated protective effect against vascular injury.

AIMS High serum phosphorus levels are a common problem in patients receiving long-term dialysis treatment. Lanthanum carbonate (Fosrenol) is a new non-aluminum, non-calcium phosphate binder developed for the treatment of hyperphosphatemia in patients with end-stage renal disease (ESRD). We report data from a recent trial, which, for the first time, assessed the efficacy and tolerability of lanthanum carbonate treatment, compared with placebo, in Chinese patients with ESRD. PATIENTS AND METHODS Following a one- to three-week washout phase and a four-week, open-label lanthanum carbonate dose-titration phase, male and female hemodialysis patients were randomized (1:1) to receive either lanthanum carbonate or placebo for four weeks. The primary efficacy parameter of the study was the control of serum phosphorus levels (< or =1.8 mmol/l [< or = 5.6 mg/dl]). Secondary endpoints included the profile of serum phosphorus during titration and parathyroid hormone, calcium, and calcium x phosphorus (Ca x P) product levels. The safety and tolerability of lanthanum carbonate were assessed by monitoring adverse events throughout the study. RESULTS Mean serum phosphorus level at the end of washout was 2.5 +/- 0.5 mmol/l (7.7 +/- 1.5 mg/dl; n=73), and there was no evidence of a difference in levels between the treatment groups pre-randomization. At the end of the study, lanthanum carbonate-treated patients had significantly lower phosphorus levels (1.6 +/- 0.5 mmol/l [5.1 +/- 1.5 mg/dl]; n=30) than those receiving placebo (2.3 +/- 0.4 mmol/l [7.2 +/- 1.3 mg/dl]; n=31; p < 0.001). In addition, a significantly higher proportion of patients receiving lanthanum carbonate had controlled serum phosphorus levels (60%) compared with the placebo group (10%; p < 0.001). Ca x P product levels were also significantly lower in the lanthanum carbonate group at the end of randomized treatment (p < 0.001). Lanthanum carbonate was well tolerated; only one serious adverse event was reported, which was unrelated to treatment. CONCLUSIONS Lanthanum carbonate was shown to be an effective and well-tolerated phosphate binder for the treatment of hyperphosphatemia in Chinese patients with ESRD. This finding supports the results of previous US and European studies, which have also shown that lanthanum carbonate treatment effectively controls serum phosphorus levels.

Left ventricular mass and hemodynamic overload in normotensive hemodialysis patients. Background It remains uncertain whether the hemodynamic parameters are important determinants of left ventricular mass (LVM) in normotensive chronic hemodialysis (NTHD) patients, as has been found in their hypertensive counterparts. Methods Forty NTHD patients (mean age, 53.7 ± 14.4 years; male/female, 18/22) without the requirement of antihypertensive drugs for at least six months were studied. Controls were 41 hypertensive hemodialysis patients (HTHD) and 46 normotensive subjects with normal renal function (NTNR). The influence of anthropometrics, cardiovascular structure and function, and volume status on LVM (by two-dimensional echocardiography) was analyzed by steps of multiple linear regression. Results As compared with the NTNR and NTHD group, the HTHD group had obvious pressure and volume/flow overload, and greater LV wall thickness, chamber size and mass. In contrast, NTHD subjects had similar blood pressure, large artery function, LV chamber size and stroke volume as the NTNR subjects. However, the NTHD patients still had greater wall thickness and LVM, along with greater cardiac output, lower total peripheral resistance and lower end-systolic meridional stress to volume ratio (ESSV) than the NTNR group. LVM in the NTHD group was significantly positively related to averaged systolic blood pressure (SBPavg), body surface area, extracellular fluid (ECF), carotid intima-media thickness (IMT), aortic pulse wave velocity (PWV), and negatively related to ESSV and Kt/V. The independent significant noncardiac structural determinants of LVM in NTHD subjects were ESSV, SBPavg, PWV and SV (model r 2 = 0.617, P Conclusions The NTHD patients, without significant pressure and volume overload, still had increased LVM that was partially explained by the persistent flow overload and subclinical LV dysfunction.

Background. Hyperphosphataemia contributes to sec-ondary hyperparathyroidism and renal osteodystrophyin patients with end-stage renal disease (ESRD).Calcium salts are widely employed to bind dietaryphosphate (P) but they may promote positive netcalcium balance and metastatic calcification. Werecently reported that ferric compounds bind intestinalphosphate in studies of normal and azotemic rats.Methods. To extend this observation, we performed anopen-label, random order, crossover comparison studyof ferric citrate and calcium carbonate in haemodia-lysis patients from two teaching hospitals. The studysample consisted of 23 women and 22 men with anaverage age of 52.5"11.8 (SD) years and an averageweight of 54.5"10.7 kg. All forms of iron therapy werediscontinued. Two weeks before the study, patientswere instructed to discontinue all P-binding agents.The patients were randomly assigned to receive eithercalcium carbonate (3 guday) or ferric citrate (3 guday)for 4 weeks followed by a 2 week washout period, andthen crossed over to the other P-binding agent for4 weeks.Results. From a baseline concentration of 5.6"1.5 mgudl, the serum P increased during the washoutperiod to 7.2"1.9 mgudl prior to calcium carbonatetreatment, and to 6.7"1.9 mgudl prior to ferric citratetreatment. The serum P concentration fell signific-antly during treatment with both calcium carbonate(7.2"1.9 to 5.2"1.5 mgudl, P-0.0001) and ferriccitrate (6.7"1.9 to 5.7"1.6 mgudl, P-0.0001). Theresults were not influenced by order of treatment.Under the conditions of the study protocol, ferriccitrate was less effective than calcium carbonateat lowering the serum phosphate concentration.The serum Ca concentration increased during treat-ment with calcium carbonate but not ferric citrate.Ferric citrate treatment did not affect the serumconcentration of aluminium. Ferric citrate treatmentwas associated with mild and generally tolerablegastrointestinal symptoms.Conclusion. Ferric citrate shows promise as a meansof lowering the serum phosphate concentration inhaemodialysis patients. Further studies are needed tofind the optimal dose.Keywords: ferric citrate; haemodialysis; open-labelcrossover study; phosphate-binding agent

Patients with end-stage renal disease undergoing regular dialysis are prone to encephalopathy, but the cause is often unclear. Dialysis patients are at risk for thiamine deficiency, which may mimic many uremic complications, including encephalopathy. To determine whether unexplained encephalopathy in regular dialysis patients is associated with thiamine deficiency, we conducted a prospective study that enrolled 30 consecutive dialysis patients with altered mental status admitted to a referred hospital during a 1-year period. A complete history, physical and neurological examinations, laboratory investigations, and computed tomographic scans or magnetic resonance imaging of the brain were obtained for each subject. In 10 of the 30 patients, diagnoses remained obscure after the initial workup. Manifestations included confusion, chorea, acute visual loss, rapidly progressive dementia, myoclonus, convulsions, and coma. Intravenous thiamine was administered to these 10 patients. All 10 patients had thiamine deficiency confirmed by a marked response to thiamine supplementation and/or a low serum thiamine concentration (35.3 +/- 6.0 nmol/L; normal, >50 nmol/L). Nine patients recovered, but one patient failed to respond because of delayed treatment. We conclude that in regular dialysis patients, unexplained encephalopathy can be mainly attributed to thiamine deficiency. This condition is fatal if unrecognized and can be successfully treated with prompt thiamine replacement.

Central vein stenosis is an indolent and underestimated complication of permanent pacemaker placement. It leads to serious problems in hemodialysis patients when arteriovenous (AV) fistulae/grafts were created at the ipsilateral arm. We, herein, reported 3 cases of AV access failure resulting from permanent pacemaker-related central vein stenosis. The pathogenesis, clinical manifestations, radiological findings, and therapeutic solution on this issue are discussed. It is mandatory to place the AV fistula/graft and permanent pacemaker wire on the opposite side for prevention of the high risk of AV access failure.

Objective To investigate the induction of nitric oxide synthase type II (iNOS) in human peritoneal mesothelial cells (HPMC) using cytokines and bacterial lipopolysaccharide (LPS). Design Confluent monolayers of HPMC were exposed to cytokines [tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), interferon gamma (IFNγ)] or LPS, individually or in various double and triple combinations, for 24 – 72 hours. Concentrations of nitrate and nitrite in the media were quantified using the Griess reaction and used as indirect indices of nitric oxide (NO) production. The expression of iNOS was assessed using reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot. Results Neither single cytokines nor LPS was able to induce iNOS mRNA or NO production. Both double combinations of TNFα+ IFNγ and IL-1β + IFNγ were able to induce iNOS mRNA expression, but only TNFα + IFNγ induced significant NO production. The triple combination of TNFα + IFNγ + IL-1β induced even more NO production than TNFα + IFNγ. There was no constitutive NO synthase type III (eNOS) expression in HPMC. Conclusions Certain combinations of cytokines could stimulate cultured HPMC to produce NO, and HPMC might be a source of intraperitoneal NO production during peritonitis.

1996. He suVered from malar rashes and photosensitivity for 1 month. At that time, C 3 and C 4 were 95 mg/dl ible with bullous SLE (Figure 3A and B). Because of (normal, 80‐155 mg/dl ) and 39.7 mg/dl (normal, the persistent vesicobullous eruption, five plasma 13‐37 mg/dl ), respectively. Double-stranded DNA exchanges were made on alternative days following (dsDNA) was 10 IU/ml (normal, 300 mg/dl ) and microhaematuria (RBC eruptions ( Table 1), cyclosporin (125 mg per day) was 3+/HPF ) were noted on urinalysis. A renal fine- added to azathioprine (100 mg per day) and prednisoneedle biopsy was performed. Light microscopy (LM ) lone (60 mg per day) after completion of the MTP pulse therapy. Proteinuria and lupus activity indices

Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin in hemodialysis patients with hyperferritinemia.BackgroundInadequate iron mobilization and defective iron utilization may cause recombinant erythropoietin (rEPO) hyporesponsiveness in hemodialysis (HD) patients with iron overload. We have demonstrated that intravenous ascorbic acid (IVAA), but not intravenous iron medication, can effectively circumvent the functional iron-deficient erythropoiesis associated with iron overload in HD patients. However, it is uncertain whether all HD patients with hyperferritinemia will consistently respond to IVAA and which index may indicate functional iron deficiency in the special entity. Therefore, a prospective study was conducted to establish the guidelines for IVAA adjuvant therapy.MethodsSixty-five HD patients with serum ferritin levels of more than 500 μg/liter were recruited and divided into the control (N = 19) and IVAA (N = 46) groups. IVAA patients with a hematocrit (Hct) of less than 30% received 300mg of ascorbic acid three times per week for eight weeks. Controls had a Hct of more than 30% and did not receive the adjuvant therapy. Red blood cell and reticulocyte counts, iron metabolism indices, erythrocyte zinc protoporphyrin (E-ZPP), and the concentrations of plasma ascorbate and oxalate were examined before and following the therapy.ResultsThirteen patients (four controls and nine IVAA patients) withdrew by the end of the study. Eighteen patients had a dramatic response to IVAA with a significant increase in their hemoglobin and reticulocyte index and a concomitant 24% reduction in rEPO dose after eight weeks. This paralleled a significant rise in serum iron and transferrin saturation (TS) and a fall in E-ZPP and serum ferritin (baselines vs. 8weeks, serum iron 68 ± 37 vs. 124 ± 64 μg/dl, TS 27 ± 10 vs. 48 ± 19%, E-ZPP 123 ± 44 vs. 70 ± 13 μmol/mol heme, and serum ferritin 816 ± 435 vs. 587 ± 323 μg/liter, P < 0.05). Compared with responders, mean values of hemoglobin, rEPO dose, iron metabolism parameters, and E-ZPP showed no significant changes in controls (N = 15) and in non-responders (N = 19). Thirty-seven patients (18 responders and 19 non-responders) were further analyzed by receiver operating characteristic curves to seek the criteria for prediction of a response to IVAA treatment. The results showed that E-ZPP at a cut-off level of more than 105 μmol/mol heme and TS at a level of less than 25% were more specific to confirm the status of functional iron deficiency in iron-overloaded patients. The two criterion values had the highest accuracy to predict a response to treatment.ConclusionsFunctional iron-deficient erythropoiesis plays a role in rEPO-hyporesponsive anemia in HD patients with hyperferritinemia. IVAA may be an adjuvant therapy for rEPO in these patients, and E-ZPP of more than 105 μmol/mol heme and TS of less than 25% should be used to guide the IVAA treatment.

Erythropoietin hyporesponsiveness: From iron deficiency to iron overload. Iron deficiency is the most frequently encountered cause of suboptimal response to recombinant human erythropoietin (rHuEPO). Carefully assessing iron status is of paramount importance in chronic renal failure patients prior to or during rHuEPO therapy. Because there is great need for iron in the EPO-stimulated erythroid progenitors, it is essential that serum ferritin and transferrin saturation levels should be maintained over 300 μg/liter and 30%, respectively. Investigators have shown that oral iron is unlikely to keep pace with the iron demand for an optimal rHuEPO response in uremics. Therefore, patients with iron deficiency will always require intravenous iron therapy. The early and prompt iron supplementation can lead to reductions in rHuEPO dose and hence cost. After the iron deficiency has been corrected or excluded, we must remember all of the possible causes of hyporespon-siveness in every rHuEPO-treated patient. As dose requirements vary, it is not clear which dose of rHuEPO causes this hyporesponsiveness. However, if the patient with iron repletion does not respond well after the induction period, the major causes blunting the response to rHuEPO should be investigated. Most factors are reversible and remediable, except resistant anemia associated with hemoglobinopathy or bone marrow fibrosis, which requires a further increase in the rHuEPO dose. By means of early detection and correction of the possible causes, the goal of increasing therapeutic efficacy can be achieved. Iron overload may lead to an enhanced risk for infection, cardiovascular complication, and cancer. Over-treatment with iron should be avoided in dialysis patients, despite the fact that the safe upper limit of serum ferritin to avoid iron overload is not clearly defined. On the other hand, functional iron deficiency may develop even when serum ferritin levels are increased. Controversy remains as to whether intravenous iron therapy can overcome this form of hyporesponsiveness in iron-overloaded patients. Moreover, a treatment option of iron supplementation is not warranted in these patients, as the potential hazards of iron overload will be worsened. We demonstrated that the mean hematocrit significantly increased from 25.1 ± 0.9% to 31 ± 1.2% after eight weeks of intravenous ascorbate therapy (300 mg three times a week) in 12 hemodialysis patients with serum ferritin levels of more than 500 μg/liter. The enhanced erythropoiesis paralleled with a rise in transferrin saturation (27.8 ± 2.5% vs. 44.8 ± 9.5%, P < 0.05) and reductions in erythrocyte zinc protoporphyrin (130 ± 32 vs. 72 ± 19 mmol/mol heme, P < 0.05) and monthly rHuEPO dose (24.2 ± 4.5 vs. 16.8 ± 3.4 3 103units, P < 0.05) at the end of study. It is speculated that ascorbate supplementation not only facilitates the iron release from storage sites and its delivery to hematopoietic tissues, but also increases iron utilization in ery-throid cells. Our study provides a more complete understanding of the pathogenesis of iron overload-related anemia and the development of an adjuvant therapy, intravenous ascorbic acid, to the existing treatments.

Tubular epithelial-myofibroblast transdifferentiation in progressive tubulointerstitial fibrosis in 5/6 nephrectomized rats. Background Tubulointerstitial fibrosis is the final common pathway to end-stage renal failure. The present study investigated the potential role of tubular epithelial cells (TEC) in progressive fibrosis in the rat remnant kidney model. Methods Rats underwent 5/6 nephrectomy or a sham operation (control), and groups of six animals were killed at weeks 1, 3, 5, 9, 13, 17 and 21. Results Immunohistochemistry staining and in situ hybridization at week 3 after nephrectomy demonstrated de novo expression of alpha-smooth muscle actin ( α -SMA)–a marker of smooth muscle cells and myofibroblasts–by TEC that was invariably associated with disruption of the tubular basement membrane (TBM). This phenotypic evidence of tubular epithelial-myofibroblast transdifferentiation was supported by ultrastructural studies identifying the presence of characteristic actin microfilaments and dense bodies within TEC with a transformed morphology. In the late stage of this apparent tubular epithelial-myofibroblast transdifferentiation, TEC lost apical-basal polarity and tight junctions, became elongated, detached from the TBM, separated from neighboring cells and appeared to migrate into the peritubular interstitium through the damaged basement membrane. Indeed, focal peritubular accumulation of α -SMA + myofibroblasts and local tubulointerstitial fibrosis was closely associated with α -SMA + tubules, suggesting a tubular epithelial origin for some of these cells. Quantitative analysis found a significant correlation between the number of α -SMA + TEC and the accumulation of interstitial α -SMA + myofibroblasts and the severity of tubulointerstitial fibrosis (both P Conclusions This study provides phenotypic and morphological evidence to support the hypothesis that TEC are pro-fibrogenitor cells capable of tubular epithelial-myofibroblast transdifferentiation in progressive renal fibrosis. In addition, we postulate that disruption of the TBM, which facilitates epithelial cell contact with the interstitial matrix, promotes this process of transdifferentiation.

Objective To investigate the prevalence of nodular goiter and thyroid dysfunction in uremic patients undergoing hemodialysis (HD) and peritoneal dialysis. Design Cross-sectional study. Setting Single dialysis unit and outpatient clinic. Patients The study included 221 patients [143 HD and 78 continuous ambulatory peritoneal dialysis (CAPD) patients] along with 135 consecutively selected outpatients as controls. Main Outcome Measures Ultrasonography was used to detect patients’ thyroid function and nodular goiter. Results Nodular goiter was detected in 54.8% of the uremic patients and in 21.5% of the controls. Uremic patients had higher prevalence of thyroid dysfunction, which included reduced serum concentration of total T3, total T4, and free T4, and increased serum level of TSH. Hypothyroidism was also observed more frequently in uremic patients than in the control group (5.4% vs 0.7%, p < 0.05). Nodular goiter was more frequently found in females than in males (63.5% vs 48%, p < 0.05). Moreover, the prevalence of nodular goiter increased with age (p < 0.02) in uremic patients. Hemodialysis patients had a higher frequency of reduced total T3 level (46.9% vs 29.5%, p < 0.02). However, CAPD patients had lower T4 levels (6.23 ± 1.82μg/dL vs 7.15± 1.99μg/dL, p < 0.05). Conclusion Because of the high incidence of hypothyroidism and nodular goiter in uremic patients, screening of thyroid function and goiter detection with ultrasound should be considered in evaluation of end-stage renal disease patients.

Spiral computed tomographic angiography (CTA), a new noninvasive imaging technique, was used to study 10 arteriovenous fistulas (AVF) in 9 hemodialysis patients. Digital subtraction angiography (DSA) was also performed as a gold standard for comparison. AVF stenosis was graded by a four-point scale: grade 0, well patency of supplying artery, anastomosis and drainage vein; grade 1

ObjectiveTo investigate the modulation of superoxide dismutase, glutathione peroxidase, and catalase by cytokines and endotoxin in human peritoneal mesothelial cells.DesignCultured human peritoneal mesothelial cells were treated with various concentrations of interleu kin-1 α, tumor necrosis factor-α(TNFα), interleukin-6, interleukin-8, transforming growth factor-β (TGFβ), and lipopolysaccharide. Cell morphology was observed and the activities of superoxide dismutase, catalase, and glutathione peroxidase were assayed. The antioxidant enzyme activities of human peritoneal mesothelial cells were also compared with those of human liver and kidney tissues.ResultsInterleukin-1α, TNFα, TGFβ, and lipopolysaccharide caused dose-dependent cytotoxicities in mesothelial cells. The activities of these three antioxidant enzymes did not change after treatment with cytokines and endotoxin. The total superoxide dismutase activity of confluent human peritoneal mesothelial cells was found to be greater than that of human liver and kidney tissues and was composed mostly of manganese superoxide dismutase activity. Furthermore, glutathione peroxidase and catalase activities of human peritoneal mesothelial cells were lower than those of human liver and kidney tissues.ConclusionIn human peritoneal mesothelial cells, lack of induction of antioxidant enzymes by inflammatory cytokines, as well as high superoxide dismutase activity accompanied by insufficient glutathione peroxidase and catalase activities may both contribute to the susceptibility of these cells to oxidative damage. Therefore, appropriate management to decrease oxidative injury to the peritoneum should be taken into consideration when treating long-term continuous ambulatory peritoneal dialysis patients.

BACKGROUND The objective of this study was to evaluate the interaction between the length polymorphism of the guanosine thymidine repeat [(GT)n] in the heme oxygenase-1 (HO-1) gene and far-infrared (FIR) therapy on access flow (Qa) and arteriovenous fistula (AVF) patency in hemodialysis (HD) patients. METHODS A total of 280 HD patients were randomized into a control group (n = 141) and the FIR group (n = 139) who received 40 min of FIR therapy three times weekly for a year during the study period from May 2005 to December 2007. Access flow was measured during HD. The [(GT)n] was determined with the definition of long (L) allele as [(GT)n] ≥ 30 and short (S) allele as [(GT)n] < 30. RESULTS The Qa decreased from S/S to S/L and further to the L/L group but increased by FIR therapy with the highest Qa increase in the S/S group. The incidence of AVF malfunction decreased both from the L/L, S/L to S/S group (32.4 versus 17.2 versus 10.9%, P = 0.007) and from the control group to FIR group (27.5 versus 12.6%, P = 0.004). Significant associations were found between AVF malfunction and the following factors (hazard ratio, P-value): a past history of AVF malfunction (2.45, P = 0.044), FIR therapy (0.369, P = 0.03) and L/L genotypes of HO-1 (2.531 versus S/S + S/L genotypes). The 1-year unassisted patency decreased from 91.9 and 77.6% in S/S and S/L subgroups with and without FIR therapy to 75.8 and 60% for L/L subgroup with and without FIR therapy, respectively (P < 0.001). CONCLUSIONS FIR therapy improves Qa and patency of AVF in HD patients, with the best protective effect in those with S/S genotype of HO-1.

Previous studies have shown that nonsteroidal anti-inflammatory drug (NSAID) use might be associated with a lower risk of developing cancer in the general population. Patients on dialysis have increased risk for cancer, but there are no studies to determine the relationship between NSAID use and cancer risk in these patients. To identify any association between NSAID use and cancer risk in patients with end-stage renal disease on dialysis, we used Taiwan's National Health Insurance database to conduct a nationwide population-based, propensity score–matched cohort study. All cancers between groups were compared by Cox proportional hazards models. Compared to nonuse of NSAIDs, the use of non-COX-2-selective inhibitors (hazard ratio 0.81, 95% confidence interval 0.67–0.97) or COX-2-selective inhibitors (0.78, 0.62–0.98) was associated with a lower risk of developing cancer. NSAID use reduced the risk of respiratory (0.39, 0.19–0.79), breast (0.41, 0.19–0.89), kidney (0.58, 0.38–0.88), digestive tract (0.64, 0.49–0.85), and bladder cancers (0.73, 0.55–0.96). NSAID use, however, significantly increased risk for upper gastrointestinal bleeding (odds ratio, 1.15, 1.07–1.23) but not adverse cardiac or cerebrovascular events. Thus, NSAID use was associated with a lower risk of developing cancer in chronic dialysis patients; however, they should still be used with caution due to the side effects of gastrointestinal bleeding.

Background The blood pressure (BP) of a proportion of chronic hemodialysis (HD) patients rises after HD. We investigated the influence of postdialysis BP rise on long-term outcomes. Methods A total of 115 prevalent HD patients were enrolled. Because of the fluctuating nature of predialysis and postdialysis BP, systolic BP (SBP) and diastolic BP before and after HD were recorded from 25 consecutive HD sessions during a 2-month period. Patients were followed for 4 years or until death or withdrawal. Results Kaplan-Meier estimates revealed that patients with average postdialysis SBP rise of more than 5 mmHg were at the highest risk of both cardiovascular and all-cause mortality as compared to those with an average postdialysis SBP change between -5 to 5 mmHg and those with an average postdialysis SBP drop of more than 5 mmHg. Furthermore, multivariate Cox regression analysis indicated that both postdialysis SBP rise of more than 5 mmHg (HR, 3.925 [95% CI, 1.410-10.846], p = 0.008) and high cardiothoracic (CT) ratio of more than 50% (HR, 7.560 [95% CI, 2.048-27.912], p = 0.002) independently predicted all-cause mortality. We also found that patients with an average postdialysis SBP rise were associated with subclinical volume overload, as evidenced by the significantly higher CT ratio (p = 0.008). Conclusions A postdialysis SBP rise in HD patients independently predicted 4-year cardiovascular and all-cause mortality. Considering postdialysis SBP rise was associated with higher CT ratio, intensive evaluation of cardiac and volume status should be performed in patients with postdialysis SBP rise.

Background and Aims: Mesenteric ischemia is an uncommon disorder associated with an extremely high mortality rate. Only limited studies have evaluated this lethal disease among patients with end-stage renal disease (ESRD). The objective of this study was to evaluate the risks of mesenteric ischemia among ESRD patients and compare the incidence between two dialysis modalities. Methods: Records of all ESRD patients older than 20 years of age from 1998 to 2007 and a control group consisting of 1 million records were retrieved from the Taiwan National Health Insurance Research Database. Hospitalizations for mesenteric ischemic events were retrieved using ICD-9-CM diagnosis codes and ICD-9-CM operation codes from inpatient claims. Results: Among 55,807 incident ESRD patients who received hemodialysis or peritoneal dialysis, there were 458 mesenteric ischemic events, corresponding to an incidence rate of 2.7 per 1,000 patient-years. Multivariate Cox regression analysis indicated that the independent risk factors were old age (HR 1.42 per 10 years), diabetes (HR 2.85), peripheral vascular disease (HR 2.66), atrial fibrillation (HR 2.15), heart failure (HR 1.65), chronic pulmonary disease (HR 1.41), neoplasm (HR 1.54), peptic ulcer disease (HR 1.86), and peritoneal dialysis (HR 1.51, all p < 0.05). There was no effect of dialysis modality on the mesenteric ischemia mortality rate. Conclusion: The risk of mesenteric ischemia for ESRD patients was 44.1 (95% confidence interval 13.4–106.2, p < 0.001) times higher than that of the general population. Compared to hemodialysis, peritoneal dialysis was associated with a higher risk of mesenteric ischemia.

From 2006 to 2010, 20 of 244 patients who underwent placement of a straight two-cuffed Tenckhoff PD catheter experienced acute pericannular bleeding. The first management strategy failed in 6 patients (30%). The second management strategy was applied in those 6 patients, and the bleeding stopped within 24 hours. Blood transfusion was not required, and no exit-site infection was detected during follow-up. Postoperative pericannular bleeding is considered to have both medical and surgical causes. From the medical point of view, patients who undergo PD catheter insertion usually have coagulation dysfunction even if the results of regular blood tests are normal. From the surgical point of view, the bleeders are usually located near the external cuff, because the Dacron cuff easily sticks over the subcutaneous layer, with the bleed developing after tissue rub. Such bleeds are usually too deep to check, and conservative management appears cost effective. Postoperative acute pericannular bleeding is usually regarded as a self-limiting condition, and it is seldom recorded. Pericannular bleeding leading to hematoma formation increases the risk of catheter-related infection and may compromise catheter survival. Although our strategies are effective in stopping bleeding, they still have potential risks for catheter injury and pericatheter infection. Standard skin sterilization and meticulous injection techniques are important.

Aims We investigated dialysis duration, dose of erythropoietin (EPO), and clinical manifestations in peritoneal dialysis (PD) patients with subclinical hypothyroidism. Methods This cross-sectional study, performed in 3 centers, assessed 122 adult patients on PD for more than 6 months with regard to demographic data, dialysis duration, thyroid function, biochemical data, EPO dose, and clinical manifestations. Thyroid dysfunction was determined by serum thyroid-stimulating hormone, free thyroxine, total thyroxine, total triiodothyronine, antithyroid peroxidase antibodies, and auto-antibodies against thyroglobulin. Results Of the 122 study patients, 98 (80.3%) were assessed as having euthyroidism; 19 (15.6%), subclinical hypothyroidism; and 5 (4.1%), subclinical hyperthyroidism. The proportion of women (74.2% vs. 57.1%, p = 0.038), the mean duration of PD (58.1 months vs. 37.9 months, p = 0.032), and the weighted mean monthly EPO dose (1.22 μg/kg vs. 1.64 μg/kg, p = 0.009) were significantly higher in the subclinical hypothyroidism group than in the euthyroidism group, but the prevalences of coronary artery disease and cerebrovascular disease were not. From the multivariate model, PD duration was more significant than sex as a risk factor for subclinical hypothyroidism ( p = 0.0132). Conclusions Subclinical hypothyroidism is frequent in PD patients, especially female patients and patients with a longer PD duration. Compared with euthyroid patients, patients with subclinical hyperthyroidism need a higher dose of EPO to maintain a stable hemoglobin level.