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Uremic pruritus with elevated levels of calcium phosphate (CaP) in skin is a common symptom in patients with chronic kidney disease (CKD). In this study, we demonstrate that intradermal injection of CaP into mice triggered scratching by up-regulating the IL-6 in skin and phosphorylation of ERKs in dorsal root ganglion (DRG) in a dose-dependent manner. IL-6 is essential because the CaP-induced up-regulation of phosphorylated (p)-ERK in DRG was considerably reduced in the IL-6 knockout mice. Microarray analysis in conjunction with real-time PCR revealed a higher mRNA expression of Bruton’s tyrosine kinase (BTK) gene in DRG after CaP injection. The inhibition of BTK by ibrutinib noticeably diminish the CaP-induced up-regulation of IL-6 and p-ERK in mice. A high amount of IL-6 was detected in itchy skin and blood of patients with CKD. The expressions of p-BTK and p-ERK in DRG primary cells reached maximum levels at 1 and 10 min, respectively, after treatment of recombinant IL-6 and were significantly reduced by treatment of IL-6 along with ibrutinib. The mechanism by which the CaP-induced pruritus mediated by the IL-6/p-BTK/p-ERK signaling was revealed.—Keshari, S., Sipayung, A. D., Hsieh, C.-C., Su, L.-J., Chiang, Y.-R., Chang, H.-C., Yang, W.-C., Chuang, T.-H., Chen, C.-L., Huang, C.-M. IL-6/p-BTK/p-ERK signaling mediates calcium phosphate–induced pruritus.

The incidence of urothelial carcinoma (UC) is higher in patients undergoing chronic dialysis than in the general population. This study investigated plasma miRNA profiling as the ancillary diagnosis biomarker associated with UC in patients undergoing chronic hemodialysis. We successfully screened out and detected miRNA expression from plasma in eight patients undergoing dialysis through quantitative real-time PCR array analysis and identified eight candidate miRNAs. The candidate miRNAs were then validated using single quantitative RT-PCR assays from 52 plasma samples. The miRNA classifier for ancillary UC detection was developed by multiple logistic regression analyses. Moreover, we validated the classifier by testing another nine samples. Expression levels of miR-150-5p, miR-150-5p/miR-155-5p, miR-378a-3p/miR-150-5p, miR-636/miR-150-5p, miR-150-5p/miR-210-3p, and miR-19b-1–5p/miR-378a-3p were shown to be significantly different between UC and non-UC samples ( P = 0.035, 0.0048, 0.016, 0.024, 0.038, and 0.048). Kaplan-Meier curve analysis also showed that low miR-19b-1-5p expression was associated with a worse prognosis ( P = 0.0382). We also developed a miRNA classifier based on five miRNA expression levels to predict UC and found that the area under curve was 0.882. The classifier had a sensitivity of 80% (95% confidence interval: 0.5191% to 0.9567%) and a specificity of 83.7% (95% confidence interval: 0.6799% to 0.9381%). This classifier was tested by nine samples with 100% accuracy. The miRNA classifier offers higher sensitivity and specificity than the existing makers. Thus, this approach will improve the prospective diagnosis of UC in patients undergoing chronic hemodialysis.

Pruritus and inflammation associated with accumulation of calcium phosphate (CaP) under the skin are common problems among dialysis patients with chronic kidney disease (CKD). The role of skin commensal microbiota in the CaP-induced uremic pruritus remains uncharacterized. Skin Cutibacterium acnes (C. acnes) can solubilize CaP by the production of short-chain fatty acids (SCFAs), such as butyric acid, through glucose fermentation. Like butyric acid, the N-[2-(2-Butyrylamino-ethoxy)-ethyl]-butyramide (BA-NH-NH-BA), a butyric acid derivative, remarkably induced acetylation of histone H3 lysine 9 (AcH3K9) in keratinocytes. Topical application of fermenting C. acnes, butyric acid or BA-NH-NH-BA onto mouse skin effectively ameliorated CaP-induced skin itching, interleukin (IL)-6 up-regulation in keratinocytes, and extracellular signal-regulated kinase (ERK) 1/2 activation in dorsal root ganglia (DRG). Activation of ERK 1/2 by CaP was markedly reduced in IL-6 knockout mice. Genus Cutibacterium was detected in relatively low abundance in itchy skin of patients with CKD. Our results identify a role for the skin fermenting C. acnes in ameliorating CaP-induced activation of IL-6/p-ERK signaling and resulting skin inflammation. Furthermore, we provide evidence for the potential therapeutic efficacy of BA-NH-NH-BA as a postbiotic for the treatment of uremic pruritus.

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.

Introduction: Hand ischemia following vascular access surgery is an uncommon complication. A clinical dilemma exists between prioritizing the preservation of vascular access and the need for surgical intervention to rescue the ischemic hand. Report: An 80 year old man who had hand ischemia following creation of a polytetrafluoroethylene arteriovenous graft with clinical evidence of ischemic pain of the left hand and Doppler ultrasound evidence of diastolic flow reversal is described. Far infrared therapy (FIR) was applied over the distal part of the affected limb, and the symptoms and signs of ischemia improved remarkably. Follow up ultrasonography also revealed the disappearance of diastolic flow reversal. Discussion: FIR therapy is a promising and non-invasive therapeutic modality to treat vascular access related hand ischemia by decreasing vascular resistance and improving hand perfusion Keywords: Arteriovenous graft, Dialysis access associated steal syndrome, Far infrared therapy, Hand ischemia, Hemodialysis, Steal syndrome

Background— Substantial infective endocarditis (IE)–related morbidity and mortality may occur even after successful treatment. However, no previous study has explored long-term hard end points (ie, stroke, myocardial infarction, heart failure, cardiovascular death) in addition to all-cause mortality in IE survivors. Methods and Results— A nationwide population-based cohort study was conducted among IE survivors identified with the use of the Taiwan National Health Insurance Research Database during 2000 to 2009. IE survivors were defined as those who survived after discharge from first hospitalization with a diagnosis of IE. A total of 10 116 IE survivors were identified. IE survivors were matched to control subjects without IE at a 1:1 ratio through the use of propensity scores. The primary outcomes were stroke, myocardial infarction, readmission for heart failure, and sudden cardiac death or ventricular arrhythmia. The secondary outcomes were repeat IE and all-cause mortality. Compared with the matched cohort, IE survivors had higher risks of ischemic stroke (adjusted hazard ratio [aHR], 1.59; 95% confidence interval [CI], 1.40–1.80), hemorrhagic stroke (aHR, 2.37; 95% CI, 1.90–2.96), myocardial infarction (aHR, 1.44; 95% CI, 1.17–1.79), readmission for heart failure (aHR, 2.24; 95% CI, 2.05–2.43), sudden death or ventricular arrhythmia (aHR, 1.69; 95% CI, 1.44–1.98), and all-cause death (aHR, 2.27; 95% CI, 2.14–2.40). Risk factors for repeat IE were older age, male sex, drug abuse, and valvular replacement after an initial episode of IE. Conclusion— Despite treatment, the risk of long-term major adverse cardiac events was substantially increased in IE survivors.

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.

Background To date, the outcomes of transplant tourism have not been reported extensively. In addition, data about the accuracy of urine cytology for the detection and the role of the BK virus (BKV) in the carcinogenesis of urothelial carcinoma (UC) after renal transplantation are lacking. Methods Three hundred seven patients who received deceased donor kidney transplants between January 2003 and December 2009 were retrospectively studied. The clinical parameters and outcomes between the domestic and tourist groups were compared. We also investigated the risk factors and role of BKV in the carcinogenesis of de novo UC by quantitative real-time polymerase chain reaction. Results The subjects in the tourist group were older at transplantation and had a shorter dialysis time before transplantation. There were significantly higher incidence rates of BKV viruria, Pneumocystis jiroveci pneumonia, and malignancy in the tourist group. Graft and patient survival were superior in the domestic group. A total of 43 cancers were identified, and the most common type of malignancy was UC (23 patients, 53.5%). The tourist group had a significantly higher incidence of tumors. The sensitivity and specificity of urine cytology for detecting UC were 73.9% and 94.7%, respectively. Independent predictors of UC included female sex, use of Chinese herbal medicine, and transplant tourism. Only two patients (8.7%) with UC had detectable BKV. Conclusions Transplant tourism was a risk factor for infection and de novo malignancy. Urothelial carcinoma was the most common malignancy after kidney transplantation. Regular screening for the early detection of UC by urine cytology or periodic sonographic surveys is mandatory, especially for those at high risk.

Introduction Due to lifelong immunosuppression, renal transplant recipients (RTRs) are at risk of infectious complications such as pneumonia. Severe pneumonia results in respiratory failure and is life‑threatening. We aimed to examine the influence of immunosuppressant dose reduction on RTRs with bacterial pneumonia and respiratory failure. Methods From January 2001 to January 2011, 33 of 1,146 RTRs at a single centre developed bacterial pneumonia with respiratory failure. All patients were treated using mechanical ventilation and aggressive therapies in the intensive care unit. Results Average time from kidney transplantation to pneumonia with respiratory failure was 6.8 years. In-hospital mortality rate was 45.5% despite intensive care and aggressive therapies. Logistic regression analysis indicated that a high serum creatinine level at the time of admission to the intensive care unit (odds ratio 1.77 per mg/dL, 95% confidence interval 1.01-3.09; p = 0.045) was a mortality determinant. Out of the 33 patients, immunosuppressive agents were reduced in 17 (51.5%). We found that although immunosuppressant dose reduction tended to improve in-hospital mortality, this was not statistically significant. Nevertheless, during a mean follow-up period of two years, none of the survivors (n = 18) developed acute rejection or allograft necrosis. Conclusion In RTRs with bacterial pneumonia and respiratory failure, higher serum creatinine levels were a mortality determinant. Although temporary immunosuppressant dose reduction might not reduce mortality, it was associated with a minimal risk of acute rejection during the two-year follow-up. Our results suggest that early immunosuppressant reduction in RTRs with severe pneumonia of indeterminate microbiology may be safe even when pathogens are bacterial in nature.

Objective To analyze the clinical features and outcomes of patients with posterior reversible encephalopathy syndrome (PRES), the risk factors of PRES-related intracranial hemorrhage (ICH), and all-cause mortality in patients with systemic lupus erythematosus (SLE). Methods Twenty-six episodes of PRES were identified in 23 SLE patients, using an electronic medical records database of 3,746 SLE patients. Results The prevalence of PRES was 0.69% among SLE patients. The scores of the SLE Disease Activity Index without neurologic descriptors (SLEDAI-N) were significantly elevated from baseline for a mean of 3.3 during PRES (P = 0.009). Rapidly deteriorating renal function, pulmonary hemorrhage, thrombotic microangiopathy, macrophage activation syndrome, or multiple organ dysfunction syndrome appeared during 65.4% of episodes. In 16 episodes, patients completely recovered from PRES-related symptoms within a median of 7 days. Visual impairment was reversed within 2 days in 8 of 15 patients, but impairment in other patients was protracted for up to 4 months, especially when ICH was present. Hypoalbuminemia ( 18 during a PRES attack had significantly higher mortality rates than did patients with SLEDAI-N scores ≤18 (P = 0.009 by log rank test). Conclusion PRES frequently occurs during active SLE with multiple complications. Hypoalbuminemia and thrombocytopenia may contribute to PRES-related ICH. The extraneurologic disease activity of lupus during PRES may influence the mortality rate of SLE patients.

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.

TNFRSF6B overexpression in tumors is a novel predictor for poor prognosis in various cancers; however, whether TNFRSF6B could be expressed in kidney tissues of patients with chronic kidney disease is unknown. Current established risk factors cannot fully predict the progression of chronic kidney disease, and, therefore, it is mandatory to develop a newer marker for predicting disease progression. We conducted a prospective cohort study comprised 167 patients with chronic kidney disease undergoing renal biopsy at a tertiary hospital with median follow-up of 30.5 months. Computer-assisted quantitative immunohistochemical staining analysis of TNFRSF6B in kidney tissues, the expression of α-smooth muscle actin and percentage of fibrosis in renal interstitium, estimated glomerular filtration rate, and urinary protein excretion rate were investigated. Study endpoint was a doubling of serum creatinine and/or end-stage renal failure requiring renal replacement therapy. We found that TNFRSF6B was predominantly expressed in the tubular epithelial cells of renal cortex. The higher the expression of TNFRSF6B, the more the expression of α-smooth muscle actin and fibrosis in interstitium (P

An umbrella concept addressing the relationship between chronic kidney disease (CKD) and mineral and bone disorders has been developed in recent years. Given the high prevalence of osteoporosis-related fractures in postmenopausal women with CKD, especially those undergoing chronic hemodialysis, the strategy used in the prevention and management of CKD and its associated osteoporosis in these postmenopausal women has become a topic of substantial debate. This controversy has ongoing relevance because osteoporosis results in a significant economic burden secondary to increased morbidity and mortality. The perfect goal of treatment and prevention includes both bone protection and renal protection, or at least protection of one disease without compromising the other disease. Both CKD and osteoporosis are frequently observed in the same patients, and often have parallel progression in postmenopausal women. Estrogen, the main female hormone during reproductive age, has been reported to have a protective effect on kidney fibrosis in several animal models, and is also considered one of the most effective drugs in the management of postmenopausal women with osteoporosis and prevention of osteoporosis. However, due to the many adverse events associated with the use of estrogen with and without progestin, some of which have contributed to significant morbidity and mortality, drug modification, which has had fewer reported incidences of adverse events without compromising the protective effect on both the kidney and bone, may have an easier road to acceptance. Therapeutic alternatives, such as the selective estrogen receptor modulators (SERMs), have shown the benefits of estrogen on bone, serum lipid levels, and renal protection, without any adverse effects on the breast and endometrium. The Multiple Outcomes of Raloxifene Evaluation trial (MORE) and its extension—Continuing Outcomes Relevant to Evista (CORE), a double-blind, randomized clinical trial encompassing postmenopausal women with osteoporosis, showed promising results in both bone and renal studies. Raloxifene increased bone mineral density (BMD) in the spine and femoral neck and reduced the risk of vertebral fracture. In addition, raloxifene slowed the increase in the rate of serum creatinine and also significantly slowed the decrease in the estimated glomerular filtration rate; of most importance, raloxifene use was associated with significantly fewer kidney-related adverse events. Hemodialyzed women on raloxifene treatment demonstrated increased trabecular BMD, a decrease in bone resorption markers, and a decrease in the low-density lipoprotein-cholesterol value. Thus, raloxifene and, most likely, other SERMs could be better in place of estrogen in the management of postmenopausal women with CKD and its associated osteoporosis, although much evidence should be provided in the advanced-stage CKD, especially in the Stage 5 CKD patients on dialysis.

Although thyroid diseases exist in patients with renal failure, thyroid function tests are not routine tests in patients on chronic hemodialysis (HD). Therefore, the impact of thyroid diseases on erythropoietin (EPO) dosage in HD patients is not well defined. This study evaluated the relationship between the dose of EPO and the presence or absence of thyroid dysfunction in HD patients.This study included 1013 adult patients on HD who did not have a malignancy, liver cirrhosis, thalassemia, iron deficiency, gastrointestinal bleeding, or a major operation within 6 months. Patients were characterized as being euthyroid, or having the sick euthyroid syndrome, primary hypothyroidism, subclinical hypothyroidism, hyperthyroidism, or subclinical hyperthyroidism based on thyroid function tests. Routine biochemistry profiles including an index of the efficiency of HD, along with clinical data over the previous 6-month period, were collected and analyzed. Multiple regression models were employed to assess the relationship between the dose of EPO and the presence or absence of thyroid status.The mean monthly EPO dosages were 77.7±37.0, 70.2±40.6, 90.8±68.4, 78.5±46.7, and 82.3±41.2 μg, respectively, in the sick euthyroid syndrome, euthyroid patients, hypothyroidism, subclinical hypothyroidism, and subclinical hyperthyroidism groups (p0.05). After adjustment of all other variables in multiple regression, the mean monthly EPO dosage was 19.00±8.59 μg more in hypothyroid patients compared with euthyroid patients (p=0.027). Further, considering an interaction with the presence of diabetes, the mean monthly EPO dosage in patients with either hypothyroidism or subclinical hypothyroidism and diabetes was 54.66±17.12 μg (p=0.001) and 31.51±10.38 μg more than that of euthyroid patients, respectively (p=0.002).In HD patients, the EPO dosage required to maintain the target hemoglobin level is significantly higher in patients having both hypothyroidism or subclinical hypothyroidism and diabetes than in euthyroid patients.

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.

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.

Hemodialysis (HD) is the most commonly-used renal replacement therapy for patients with end-stage renal disease worldwide. Arterio-venous fistula (AVF) is the vascular access of choice for HD patients with lowest risk of infection and thrombosis. In addition to environmental factors, genetic factors may also contribute to malfunction of AVF. Previous studies have demonstrated the effect of genotype polymorphisms of angiotensin converting enzyme on vascular access malfunction. We conducted a multicenter, cross-sectional study to evaluate the association between genetic polymorphisms of renin-angiotensin-aldosterone system and AVF malfunction. Totally, 577 patients were enrolled. Their mean age was 60 years old and 53% were male. HD patients with AVF malfunction had longer duration of HD (92.5 ± 68.1 vs. 61.2 ± 51.9 months, p < 0.001), lower prevalence of hypertension (44.8% vs. 55.3%, p = 0.025), right-sided (31.8% vs. 18.4%, p = 0.002) and upper arm AVF (26.6% vs. 9.7%, p < 0.001), and higher mean dynamic venous pressure (DVP) (147.8 ± 28.3 vs. 139.8 ± 30.0, p = 0.021). In subgroup analysis of different genders, location of AVF and DVP remained significant clinical risk factors of AVF malfunction in univariate and multivariate binary logistic regression in female HD patients. Among male HD patients, univariate binary logistic regression analysis revealed that right-side AVF and upper arm location are two important clinical risk factors. In addition, two single nucleotide polymorphisms (SNPs), rs275653 (Odds ratio 1.90, p = 0.038) and rs1492099 (Odds ratio 2.29, p = 0.017) of angiotensin II receptor 1 (AGTR1), were associated with increased risk of AVF malfunction. After adjustment for age and other clinical factors, minor allele-containing genotype polymorphisms (AA and CA) of rs1492099 still remained to be a significant risk factor of AVF malfunction (Odds ratio 3.63, p = 0.005). In conclusion, we demonstrated that rs1492099, a SNP of AGTR1 gene, could be a potential genetic risk factor of AVF malfunction in male HD patients.

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.

Objectives Pneumocystis jiroveci pneumonia is a rare but lethal complication in renal transplant recipients. Dose reduction of immunosuppressive agents in such situations is recommended, but its quantity and safety are unclear. Materials and methods From January 2001 to January 2011, twenty of one thousand forty-six renal transplant recipients in a single center developed Pneumocystis jiroveci pneumonia, which was diagnosed by the Giemsa and Gomori methenamine silver stains from a specimen of bronchoalveolar lavage. Results We found that timing of the first immunosuppressant reduction of the Pneumocystis jiroveci pneumonia survivor (mean, 1.4 days after admission) was significantly earlier than that of the deceased patient (mean, 5.1 days after admission). Logistic regression analysis indicated that for those whose immunosuppressants were reduced more aggressively (either 1 of the immunosuppressants was reduced by more than 50% within 2 days of hospitalization) were significantly more likely to survive (mortality risk, OR, 0.074 [95% CI, 0.01-0.84]; P = .035). In addition, none of the survivors developed acute rejection or allograft necrosis during a mean follow-up of 2 years. Conclusions Dosage reduction of immunosuppressive agents in renal transplant recipients with Pneumocystis jiroveci pneumonia should be prompt and sufficient. Aggressive immuno-suppressant dosage reduction is safe in such circumstance and is associated with minimal risk of in-hospital and long-term acute allograft rejection.

Acute appendicitis in patients with end-stage renal disease (ESRD) poses a diagnostic challenge. Delayed surgery can contribute to higher morbidity and mortality rates. However, few studies have evaluated this disease among ESRD patients. Our study focused on the lack of data on the incidence and risk factors of acute appendicitis among ESRD patients and compared the outcomes in patients who underwent different dialysis modalities. This national survey was conducted between 1997 and 2005 and included ESRD patients identified from the Taiwan National Health Insurance database. The incidence rate of acute appendicitis in ESRD patients was compared with that in randomly selected age-, sex-, and Charlson comorbidity score-matched non-dialysis controls. A Cox regression hazard model was used to identify risk factors. Among 59,781 incident ESRD patients, matched one-to-one with controls, there were 328 events of acute appendicitis. The incidence rate of 16.9 per 10,000 person-years in the ESRD cohort was higher than that in the control cohort (p = 0.003). The independent risk factors were atrial fibrillation (hazard ratio [HR], 2.08), severe liver disease (HR, 1.74), diabetes mellitus (HR, 1.58), and hemodialysis (HR, 1.74). Compared with the control cohort, subsequent perforation and mortality rates of acute appendicitis were also higher in the ESRD cohorts. There was no effect of dialysis modality on the patient outcomes. ESRD patients had a higher risk for acute appendicitis and poorer outcomes than non-dialysis populations. A careful examination of ESRD patients presenting with atypical abdominal pain to avoid misdiagnosis is extremely important to prevent delayed surgery.

Objectives Serum creatinine is an important clinical marker for renal clearance. However, the Jaffe method had much interference and the accuracy had not been tested in patients under hemodialysis (HD) with standard isotope dilution-liquid chromatography-mass spectrometry (IDLCMS) method. The validity of enzymatic method is also unknown. Methods The predialysis serum creatinine levels of 126 patients under regular HD for 3 months were checked by Jaffe, enzymatic, and IDLCMS methods. We compared the value of the Jaffe and enzymatic to that of IDLCMS in linear regression model. And we also tried to find the clinical parameters that influence the difference between Jaffe vs. IDLCMS and enzymatic vs. IDLCMS method. Results We found significant underestimate serum creatinine in uremic patients by Jaffe and enzymatic methods. Serum glucose and globulin are positive biases, whereas albumin, potassium, and phosphorus are negative biases. Enzymatic method is less affected by serum glucose and serum protein. Albumin acts differently in uremic serum compared to the results of mixing them with normal serum. Conclusions For uremic patients, in whom creatinine level is high and many of them suffered from diabetes mellitus, serum creatinine can be either under- or overestimated by Jaffe method. Enzymatic method is less affected and may be a better method. J. Clin. Lab. Anal. 26:206-214, 2012. © 2012 Wiley Periodicals, Inc.

Increased renal cortical echogenicity can be seen in patients with various underlying renal abnormalities. However, there are no reports of hyperechoic cortex associated with volume depletion until now. Here, we describe two cases of hyperechoic cortex caused by severe dehydration due to liver abscess and acute salmonellosis which lead to nausea, vomiting, and diarrhea. After administering large amounts of fluid supplements, the renal functions dramatically recovered and the echogenicity of the renal cortex returned to normal. Redistribution of renal blood flow and cortical ischemia may play a role in changes in echogenicity that occur in the renal cortex. Additionally, studies on increased renal cortical echogenicity and dehydration are reviewed.

Background The population of uremia patients receiving long-term peritoneal dialysis (PD) is growing, and abnormal thyroid function occurs increasingly in patients with chronic kidney disease in comparison with the normal population. We aimed to elucidate the clinical impact of abnormal thyroid function in long-term PD patients. Methods This was a retrospective, case-controlled, longitudinal study. We collected the characteristics, laboratory data, dialysis parameters, and thyroid and heart function of patients who underwent long-term PD for >8 years during the past 25 years in Taipei Veterans General Hospital, Taiwan. Patients with hyperthyroidism were excluded. None of these subjects presented a recent history of infection or inflammatory disease or took any drugs known to influence thyroid function. Abnormal thyroid function was defined as the presence of primary hypothyroidism and sick euthyroid syndrome. Results A total of 46 patients were enrolled. The mean duration of PD therapy was 147.8 (48.3) months. Nineteen of 46 (41.3%) patients had abnormal thyroid function tests. Patients with abnormal thyroid function had a worse prognosis in cumulative patient survival analysis by Kaplan–Meier method ( p = 0.02). After adjusting for diabetes mellitus, cardiothoracic ratio, C-reactive protein (CRP), and cardiovascular diseases, abnormal thyroid function remained as an independent predictor of patient survival (hazard ratio = 7.633, 95% confidence interval 1.3–43.9, p = 0.02). The CRP levels were significantly inversely correlated with free thyroxine levels ( r = –0.547; p = 0.01). The most common cause of death among the patients was sepsis (67.7%) rather than cardiovascular disease (20.0%). Conclusion PD patients with abnormal thyroid function had poor cumulative survival. Lower thyroid hormone level in PD patients was associated with high CRP levels. Physicians should be alert for the presence of abnormal thyroid function and proinflammatory status in long-term PD patients.

Objectives. Erythropoiesis-stimulating agents (ESA) are the main treatment for anemia in hemodialysis (HD) patients. We evaluated factors determining the response after treatment of a new ESA (continuous erythropoietin erythropoietin receptor activator (CERA)).Methods. 61 HD patients were classified by their response at two different timings. First, patients whose hematocrit (Hct) increased 1.5% in the first week were defined as initial responders (IR,n=16). We compared several parameters between IR and the rest of the study subjects (non-IR,n=45). Second, patients whose Hct increased 2% in the 4th week were defined as sustained responders (SR,n=12), and we did a similar comparison.Results. The Hct showed a waveform fluctuation. Compared with the rest, IR had significantly lower platelet counts and higher levels of ferritin, total protein, total bilirubin, and serum sodium, while SR had significantly lower levels of C-reactive protein and low-density lipoprotein (AllP<0.05). In comparison with the rest, higher Hct persisted for 10 weeks in SR but only for two separate weeks (the 1st and 7th week) in IR.Conclusions. The initial and sustained erythropoietic responses are independent from each other and are associated with different factors. Treatment focusing on these factors may improve the response.

In the case reported here, after prolonged medical therapy resistance, severe proteinuria subsided following bilateral renal artery embolization (RAE). Thereafter, respiratory distress, anasarca edema, muscle mass, and serum albumin level improved after regular hemodialysis. Although RAE is reported to be a safe and effective therapeutic procedure, it is rarely used for severe proteinuria with prolonged medical therapy resistance. The limited use of bilateral RAE for nephrological purposes may be partly related to its tendency to destroy renal function, which results in anuria and subsequent regular dialysis. However, delayed RAE could cause the patient to reach a life-threatening cachexic state and could increase the risk of morbidity and mortality due to severe proteinuria-induced hypoalbuminemia. Our case and selected previous reports reveal important information for physicians and patients while discussing prognoses and considering the pros and cons of bilateral RAE.

OBJECTIVE: Pneumocystis jiroveci pneumonia (PJP) infection is a rare but lethal complication in immunocompromised hosts. However, risk factors for PJP infection in glomerulonephritis (GN) patients receiving immunosuppressants are unknown. METHODS: From August 2009 to July 2010, we encountered a cluster occurrence of PJP infection in our renal biopsy patients. Seven of 73 GN patients under immunosuppressant agents developed PJP infection, which were diagnosed by the Giemsa and Gomori's methenamine silver stains of the bronchoalveolar lavage specimen. RESULTS: The average time of PJP onset was 2.4 months after immunosuppressant initiation. We found that the immunosuppressant regimens were equal between patients with and without the development of PJP infection regarding the daily dose per body weight, treatment duration, and accumulative dose per body weight. Logistic regression analysis indicated that high serum creatinine, low hemoglobin, and low absolute lymphocyte count at immunosuppressant initiation, and high chronicity indices of kidney pathology were predictors of PJP infection. In addition, patients with PJP infection had persistently worse renal function, more severe anemia, and more severe lymphocytopenia as compared to those without. CONCLUSION: Prophylactic therapy for P. jiroveci and immunosuppressant dose reduction should be considered in GN patients with high chronicity of their kidney diseases and/or persistent lymphocytopenia.

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.