LTBP4 Protects Against Renal Fibrosis via Mitochondrial and Vascular Impacts.

BACKGROUND: As a part of natural disease progression, acute kidney injury (AKI) can develop into chronic kidney disease via renal fibrosis and inflammation. LTBP4 (latent transforming growth factor beta binding protein 4) regulates transforming growth factor beta, which plays a role in renal fibrosis pathogenesis. We previously investigated the role of LTBP4 in chronic kidney disease. Here, we examined the role of LTBP4 in AKI. METHODS: LTBP4 expression was evaluated in human renal tissues, obtained from healthy individuals and patients with AKI, using immunohistochemistry. LTBP4 was knocked down in both C57BL/6 mice and human renal proximal tubular cell line HK-2. AKI was induced in mice and HK-2 cells using ischemia-reperfusion injury and hypoxia, respectively. Mitochondrial division inhibitor 1, an inhibitor of DRP1 (dynamin-related protein 1), was used to reduce mitochondrial fragmentation. Gene and protein expression were then examined to assess inflammation and fibrosis. The results of bioenergetic studies for mitochondrial function, oxidative stress, and angiogenesis were assessed. RESULTS: LTBP4 expression was upregulated in the renal tissues of patients with AKI. Ltbp4-knockdown mice showed increased renal tissue injury and mitochondrial fragmentation after ischemia-reperfusion injury, as well as increased inflammation, oxidative stress, and fibrosis, and decreased angiogenesis. in vitro studies using HK-2 cells revealed similar results. The energy profiles of Ltbp4-deficient mice and LTBP4-deficient HK-2 cells indicated decreased ATP production. LTBP4-deficient HK-2 cells exhibited decreased mitochondrial respiration and glycolysis. Human aortic endothelial cells and human umbilical vein endothelial cells exhibited decreased angiogenesis when treated with LTBP4-knockdown conditioned media. Mitochondrial division inhibitor 1 treatment ameliorated inflammation, oxidative stress, and fibrosis in mice and decreased inflammation and oxidative stress in HK-2 cells. CONCLUSIONS: Our study is the first to demonstrate that LTBP4 deficiency increases AKI severity, consequently leading to chronic kidney disease. Potential therapies focusing on LTBP4-associated angiogenesis and LTBP4-regulated DRP1-dependent mitochondrial division are relevant to renal injury.

The screening, diagnosis, and management of patients with autosomal dominant polycystic kidney disease: A national consensus statement from Taiwan.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited cause of end-stage kidney disease (ESKD) worldwide. Guidelines for the diagnosis and management of ADPKD in Taiwan remains unavailable. In this consensus statement, we summarize updated information on clinical features of international and domestic patients with ADPKD, followed by suggestions for optimal diagnosis and care in Taiwan. Specifically, counselling for at-risk minors and reproductive issues can be important, including ethical dilemmas surrounding prenatal diagnosis and pre-implantation genetic diagnosis. Studies reveal that ADPKD typically remains asymptomatic until the fourth decade of life, with symptoms resulting from cystic expansion with visceral compression, or rupture. The diagnosis can be made based on a detailed family history, followed by imaging studies (ultrasound, computed tomography, or magnetic resonance imaging). Genetic testing is reserved for atypical cases mostly. Common tools for prognosis prediction include total kidney volume, Mayo classification and PROPKD/genetic score. Screening and management of complications such as hypertension, proteinuria, urological infections, intracranial aneurysms, are also crucial for improving outcome. We suggest that the optimal management strategies of patients with ADPKD include general medical care, dietary recommendations and ADPKD-specific treatments. Key points include rigorous blood pressure control, dietary sodium restriction and Tolvaptan use, whereas the evidence for somatostatin analogues and mammalian target of rapamycin (mTOR) inhibitors remains limited. In summary, we outline an individualized care plan emphasizing careful monitoring of disease progression and highlight the need for shared decision-making among these patients.

The down-regulation of XBP1, an unfolded protein response effector, promotes acute kidney injury to chronic kidney disease transition.

BACKGROUND: The activation of the unfolded protein response (UPR) is closely linked to the pathogenesis of renal injuries. However, the role of XBP1, a crucial regulator of adaptive UPR, remains unclear during the transition from acute kidney injury (AKI) to chronic kidney disease (CKD). METHODS: We characterized XBP1 expressions in different mouse models of kidney injuries, including unilateral ischemia-reperfusion injury (UIRI), unilateral ureteral obstruction, and adenine-induced CKD, followed by generating proximal tubular XBP1 conditional knockout (XBP1cKO) mice for examining the influences of XBP1. Human proximal tubular epithelial cells (HK-2) were silenced of XBP1 to conduct proteomic analysis and investigate the underlying mechanism. RESULTS: We showed a tripartite activation of UPR in injured kidneys. XBP1 expressions were attenuated after AKI and inversely correlated with the severity of post-AKI renal fibrosis. XBP1cKO mice exhibited more severe renal fibrosis in the UIRI model than wide-type littermates. Silencing XBP1 induced HK-2 cell cycle arrest in G2M phase, inhibited cell proliferation, and promoted TGF-ß1 secretion. Proteomic analysis identified TNF receptor associated protein 1 (Trap1) as the potential downstream target transcriptionally regulated by XBP1s. Trap1 overexpression can alleviate silencing XBP1 induced profibrotic factor expressions and cell cycle arrest. CONCLUSION: The loss of XBP1 in kidney injury was profibrotic, and the process was mediated by autocrine and paracrine regulations in combination. The present study identified the XBP1-Trap1 axis as an instrumental mechanism responsible for post-AKI fibrosis, which is a novel regulatory pathway.

Computed tomography-based sarcopenia in patients receiving peritoneal dialysis: Correlation with lean soft tissue and survival.

BACKGROUND/PURPOSE: We evaluated whether the results of the computed tomography (CT)-based sarcopenia assessment were correlated with edema-free lean soft tissue (LST) and were associated with the prognosis of patients receiving peritoneal dialysis (PD). METHODS: We conducted a prospective cohort study and enrolled patients aged >20 years who started to undergo PD between February 2009 and February 2012. All patients underwent LST evaluation and non-contrast abdominal CT for assessing the total skeletal muscle (TSM) and psoas muscle (PM) indices at the level of the third lumbar vertebra. We analyzed the correlation between LST and CT assessment of muscle mass. Then we determined optimal sex-specific cutoff values for TSM-defined and PM-defined sarcopenia to predict mortality, aided by the maximally selected rank statistics. RESULTS: A total of 158 patients were enrolled, of whom 41 (25.9%) and 65 (41.1%) had sarcopenia based on the TSM and PM indices, respectively. LST was significantly strong correlated with TSM and PM indices (r = 0.517, p < 0.001 and r = 0.688, p < 0.001, respectively). In univariate and multivariate analyses after adjusting clinical and PD-related parameters, only patients with PM-defined sarcopenia had poorer survival than did those without (hazard ratio [HR]: 2.386, 95% confidence interval [CI]: 1.315-4.330), but patients with TSM-defined sarcopenia did not show a poorer survival (HR: 1.608, 95% CI: 0.860-3.006). CONCLUSION: Sarcopenia assessment based on CT was strongly correlated with LST and PM-defined sarcopenia indicated poor prognosis in patients receiving long-term PD.

Early elimination of uremic toxin ameliorates AKI-to-CKD transition.

Acute kidney injury (AKI)-related fibrosis is emerging as a major driver of chronic kidney disease (CKD) development. Aberrant kidney recovery after AKI is multifactorial and still poorly understood. The accumulation of indoxyl sulfate (IS), a protein-bound uremic toxin, has been identified as a detrimental factor of renal fibrosis. However, the mechanisms underlying IS-related aberrant kidney recovery after AKI is still unknown. The present study aims to elucidate the effects of IS on tubular damage and its involvement in the pathogenesis of AKI-to-CKD transition. Our results showed that serum IS started to accumulate associated with the downregulation of tubular organic anion transporter but not observed in the small-molecule uremic toxins of the unilateral ischemia-reperfusion injury (UIRI) without a contralateral nephrectomy model. Serum IS is positively correlated with renal fibrosis and binding immunoglobulin protein (BiP) and CAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) expression induction in the UIRI with a contralateral nephrectomy model (UIRI+Nx). To evaluate the effects of IS in the AKI-to-CKD transition, we administered indole, a precursor of IS, at the early stage of UIRI. Our results demonstrated IS potentiates renal fibrosis, senescence-associated secretory phenotype (SASP), and activation of endoplasmic reticulum (ER) stress, which is attenuated by synergistic AST-120 administration. Furthermore, we clearly demonstrated that IS exposure potentiated hypoxia-reperfusion (H/R) induced G2/M cell cycle arrest, epithelial-mesenchymal transition (EMT) and aggravated ER stress induction in vitro. Finally, the ER chemical chaperon, 4-phenylbutyric acid (4-PBA), successfully reversed the above-mentioned AKI-to-CKD transition. Taken together, early IS elimination in the early stage of AKI is likely to be a useful strategy in the prevention and/or treatment of the AKI-to-CKD transition.

Frailty is associated with a higher risk of developing delirium and cognitive impairment among patients with diabetic kidney disease: A longitudinal population-based cohort study.

AIMS: Delirium, a form of acute brain failure, exhibits a high incidence among older adults. Recent studies have implicated frailty as an under-recognized complication of diabetes mellitus. Whether the presence of frailty increases the risk of delirium/cognitive impairment among patients with diabetic kidney disease (DKD) remains unclear. METHODS: From the longitudinal cohort of diabetes patients (LCDP) (n = 840,000) in Taiwan, we identified adults with DKD, dividing them into those without and with different severities of frailty based on a modified FRAIL scale. Cox proportional hazard regression was utilized to examine the frailty-associated risk of delirium/cognitive impairment, identified using approaches validated by others. RESULTS: Totally 149,145 patients with DKD (mean 61.0 years, 44.2% female) were identified, among whom 31.0%, 51.7%, 16.0% and 1.3% did not have or had 1, 2 and >2 FRAIL items at baseline. After 3.68 years, 6613 (4.4%) developed episodes of delirium/cognitive impairment. After accounting for demographic/lifestyle factors, co-morbidities, medications and interventions, patients with DKD and 1, 2 and >2 FRAIL items had a progressively higher risk of developing delirium/cognitive impairment than those without (for those with 1, 2 and >2 items, hazard ratio 1.18, 1.26 and 1.30, 95% confidence interval 1.08-1.28, 1.14-1.39 and 1.10-1.55, respectively). For every FRAIL item increase, the associated risk rose by 9%. CONCLUSIONS: Frailty significantly increased the risk of delirium/cognitive impairment among patients with DKD. Frailty screening in these patients may assist in delirium risk stratification.

Risk of Skin Cancer among Patients with Chronic Kidney Disease Treated with Ultraviolet B Phototherapy for Uraemic Pruritus: A Nationwide Cohort Study.

The safety of ultraviolet B (UVB) phototherapy with respect to cutaneous carcinogenesis has not been established for patients with chronic kidney disease. To investigate this issue, a nationwide cohort study of 10,805 patients with advanced chronic kidney disease was conducted using data from the National Health Insurance of Taiwan, the Taiwan Cancer Registry, and the national death registry. After a median follow-up of 75 months, 16 of 2,161 patients in the UVB group and 63 of 8,644 patients in the non-UVB group developed skin cancers. Compared with the non-UVB group, patients in the UVB group did not show an increased risk of skin cancer (hazard ratio 1.066; 95% confidence interval 0.584-1.944), non-melanoma skin cancer (hazard ratio 1.067; 95% confidence interval 0.571-1.996), or cutaneous melanoma (hazard ratio 1.009; 95% confidence interval 0.115-8.879). In addition, patients who received more UVB phototherapy did not show an increased risk of skin cancer. UVB phototherapy appears to be a safe treatment for uraemic pruritus in patients with chronic kidney disease.

Frailty increases the risk for developing urinary tract infection among 79,887 patients with diabetic mellitus and chronic kidney disease.

BACKGROUND: Patients with diabetic mellitus (DM) and chronic kidney disease (CKD) are at an increased risk of urinary tract infection (UTI) due to their altered immunological integrity. These patients are similarly prone to developing frailty, a state of cumulative health deficits involving multiple domains and leading to adverse outcomes. Whether frailty predisposes affected individuals to UTI among patients with DM and CKD remains unclear. METHODS: A population-based cohort of patients with DM and CKD (n = 79,887) were assembled from the Longitudinal Cohort of Diabetes Patients, with their baseline frailty status measured by a  modified FRAIL scale. We analyzed their risk of developing UTI depending on their severity of frailty, after accounting demographic profiles, lifestyle factors, comorbidities, concurrent medications, and major interventions. A secondary analysis focused on the risk of urosepsis related to frailty. RESULTS: Among all participants, 36.1 %, 50.3 %, 12.8 %, and 0.8 % did not have or had 1, 2, and ≥ 3 FRAIL items, respectively, at baseline. After 3.51 years, 11,175 UTI events occurred. Kaplan-Meier analysis showed that participants with DM, CKD and an increasing number of FRAIL items had successively higher incidence of UTI than those without any FRAIL items (log rank p < 0.001). Cox proportional hazard modeling revealed that after accounting for all confounders, those with more severe frailty exhibited a significantly higher risk of incident UTI (for groups of 1, 2, and ≥ 3 FRAIL items, hazard ratio 1.19, 1.24, and 1.43, respectively; all p < 0.001) than those without. An 11 % risk elevation for UTI could be observed for every FRAIL item increase. Participants with more severe frailty exhibited a trend of having higher risk of urosepsis as well. CONCLUSIONS: Having frailty predicted a higher risk of developing UTI in the future in patients with DM and CKD. It would be prudent to screen for frailty in these patients and provide optimal frailty-directed management to attenuate their risk of UTI and improve their outcomes.

Gustatory Dysfunction Is Closely Associated With Frailty in Patients With Chronic Kidney Disease.

OBJECTIVE: Gustatory function is frequently impaired in patients with chronic kidney disease (CKD), and the associated taste dysfunction contributes to compromised nutrition. Whether gustatory dysfunction is an underappreciated risk factor for frailty in patients with CKD remains unclear. The objective of this work was to examine the role of gustatory dysfunction as a risk factor for frailty in patients with CKD. METHODS: We prospectively enrolled patients with stage 3 or higher CKD from a single institute, with their gustatory function assessed using both objective (taste strip method) and subjective approaches, and frailty identified using the Edmonton frail scale, FRAIL scale, and Study of Osteoporotic Fracture (SOF) scale. Multiple regression analyses were performed to investigate whether results from gustatory function tests independently correlated with frailty. RESULTS: Among the enrolled patients with CKD, 14 (17.9%) were found to be frail. We discovered that higher taste strip scores, or better taste function, were significantly associated with a lower frail probability (odds ratio [OR] 0.74 per score, 95% confidence interval [CI] 0.57-0.97), independent of clinical features, while better subjective taste function (OR 0.84 per score, 95% CI 0.74-0.96) and better oral cavity intactness (OR, 0.94; 95% CI, 0.9-0.98) were similarly associated with a lower frail probability among patients with CKD. CONCLUSION: Gustatory dysfunction may be an important risk factor for frailty in patients with CKD. It is tempting to presume that interventions aiming to ameliorate such deficits may bear the potential of reducing frailty severity in this population with a high frailty burden.

[From Peritoneal Dialysis Education Guidelines to Clinical Practice].

Peritoneal dialysis (PD) education, which has been shown to impact life quality and survival rates, is thus crucial to patients with end-stage renal disease. As medical workers in the PD field, it is our hope and obligation to lead every patient to achieve their individual self-care goals. Although the International Society of Peritoneal Dialysis (ISPD) published guidelines for peritoneal dialysis training in 2006 to help build a comprehensive educational program for better outcomes, how to implement related education programs has not yet been taken seriously by clinical health workers. In Taiwan, no articles introducing these guidelines and no report on the clinical implementation of these guidelines have been published. Thus, this article was written to describe the ISPD guidelines on PD education, including education content, space requirements, soft / hard equipment needs, training hours, and mode. Medical workers may use evaluation and periodical retraining to continuously monitor the self-care ability of patients. Aided by timely home visitations, learning outcomes and patient adaption may be followed comprehensively. Furthermore, to help patients under PD strengthen their capabilities of self-management and self-care, practical training suggestions based on the practice experience of our PD center are also included in this article as references for all medical workers in the PD field.

Applicability of laboratory deficit-based frailty index in predominantly older patients with end-stage renal disease under chronic dialysis: A pilot test of its correlation with survival and self-reported instruments.

AIM: Laboratory deficit-based frailty index (LFI) exhibited outcome-prediction ability in the elderly, but not in those with end-stage renal disease (ESRD). We hypothesized that LFI results might have outcome correlation and correlate closely with other instruments in ESRD patients. METHODS: We prospectively enroled ESRD patients between 2014 and 2015 and administered self-report frailty instruments (Strawbridge questionnaire, Edmonton frail scale (EFS), Groningen frailty indicator (GFI), Tilburg frailty indicator, G8 questionnaire and FRAIL scale), and Cardiovascular Health Study (CHS) scale, with two types of LFI calculated. They were followed up until June 30, 2017. Correlations between the results of six instruments, CHS scale, and those of LFI were identified, followed by Kaplan-Meier survival analyses and logistic regression analyses to compare those with high and low LFI. RESULTS: The frailty prevalence was 33.3% (CHS), 78.8% Strawbridge questionnaire, 45.5% (EFS), 57.6% (GFI), 27.3% (Tilburg frailty indicator), 84.8% (G8) and 18.2% (FRAIL) among ESRD participants. LFI-1 results were significantly correlated with those of LFI-2 (P < 0.01), EFS (P = 0.04) and GFI (P < 0.01), while LFI-2 results were not. Those with CHS or GFI-identified frailty had significantly lower 1,25-(OH)2 -D levels than those without. After 32.3 ± 5.4 months, patients with high LFI-1 scores, but not LFI-2, had a significantly higher mortality than those with lower scores. GFI and EFS scores were also independently associated with LFI-1, while CHS scores exhibited borderline association only. CONCLUSION: Among a group of predominantly older ESRD patients, LFI differentiates patients with good and poor outcomes, supporting its applicability in these patients.

Astaxanthin Counteracts Vascular Calcification In Vitro Through an Early Up-Regulation of SOD2 Based on a Transcriptomic Approach.

Vascular calcification (VC) is a critical contributor to the rising cardiovascular risk among at-risk populations such as those with diabetes or renal failure. The pathogenesis of VC involves an uprising of oxidative stress, for which antioxidants can be theoretically effective. However, astaxanthin, a potent antioxidant, has not been tested before for the purpose of managing VC. To answer this question, we tested the efficacy of astaxanthin against VC using the high phosphate (HP)-induced vascular smooth muscle cell (VSMC) calcification model. RNAs from treated groups underwent Affymetrix microarray screening, with intra-group consistency and inter-group differential expressions identified. Candidate hub genes were selected, followed by validation in experimental models and functional characterization. We showed that HP induced progressive calcification among treated VSMCs, while astaxanthin dose-responsively and time-dependently ameliorated calcification severities. Transcriptomic profiling revealed that 3491 genes exhibited significant early changes during VC progression, among which 26 potential hub genes were selected based on closeness ranking and biologic plausibility. SOD2 was validated in the VSMC model, shown to drive the deactivation of cellular senescence and enhance antioxidative defenses. Astaxanthin did not alter intracellular reactive oxygen species (ROS) levels without HP, but significantly lowered ROS production in HP-treated VSMCs. SOD2 knockdown prominently abolished the anti-calcification effect of astaxanthin on HP-treated VSMCs, lending support to our findings. In conclusion, we demonstrated for the first time that astaxanthin could be a potential candidate treatment for VC, through inducing the up-regulation of SOD2 early during calcification progression and potentially suppressing vascular senescence.

Efficacy of Antiplatelet Agent Usage for Primary and Secondary Prevention in Dialysis Patients: a Nationwide Data Survey and Propensity Analysis.

BACKGROUND: Although cardiovascular (CV) disease is the leading cause of mortality and morbidity in dialysis patients, there is little evidence to guide the use of antiplatelet agents in dialysis patients. METHOD: A nationwide database (Registry for Catastrophic Illnesses) for Taiwan, which has data from nearly all patients who received dialysis therapy from 1995 to 2008, was used. This is a population-based cohort study with time to event analyses to estimate the relation between antiplatelet agent use and outcomes. Hazard ratios were calculated to evaluate the effect of antiplatelet agent use on the risk of major CV events and mortality. Baseline characteristics were matched by propensity score (PS). RESULTS: A total of 71,835 were included, and 10,595 (14.7%) patients received an anti-platelet agent. The median value of follow-up days was 61.6 months. After PS-based matching, 9598 patients who used an antiplatelet agent and 23,794 non-users were included in the analysis. After PS matching, there was no difference between patients using an antiplatelet agent or not in CV events (p = 0.672) and total mortality (p = 0.529). A subgroup analysis of different usage periods of antiplatelet agents indicated that CV events and total mortality were similar in those who used antiplatelet agents for short or long durations. In subgroup analysis, there was also no difference between patients with a different modality of dialysis (hemodialysis or peritoneal dialysis), different antiplatelet agents (aspirin, clopidogrel, and/or ticlopidine) or patients with/without previous cardiovascular disease in CV events and total mortality. CONCLUSIONS: Antiplatelet agent usage does not reduce CV events and total mortality in dialysis patients.

Circulating MicroRNA-125b Predicts the Presence and Progression of Uremic Vascular Calcification.

OBJECTIVE: Vascular calcification (VC) is a major cause of mortality in patients with end-stage renal diseases. Biomarkers to predict the progression of VC early are in urgent demand. APPROACH AND RESULTS: We identified circulating, cell-free microRNAs as potential biomarkers using in vitro VC models in which both rat and human aortic vascular smooth muscle cells were treated with high levels of phosphate to mimic uremic hyperphosphatemia. Using an Affymetrix microRNA array, we found that miR-125b and miR-382 expression levels declined significantly as biomineralization progressed, but this decline was only observed for miR-125b in the culture medium. A time-dependent decrease in aortic tissue and serum miR-125b levels was also found in both ex vivo and in vivo renal failure models. We examined the levels of circulating, cell-free miR-125b in sera from patients with end-stage renal diseases (n=88) and found an inverse association between the severity of VC and the circulating miR-125b level, irrespective of age or mineral-related hormones (odds ratio, 0.71; P=0.03). Furthermore, serum miR-125b levels on enrollment can predict VC progression years later (for high versus low, odds ratio, 0.14; P<0.01; for the highest versus lowest tertile and middle versus lowest tertile, odds ratio, 0.55 and 0.13; P=0.3 and <0.01, respectively). The uremic VC prediction efficacy using circulating miR-125b levels was also observed in an independent cohort (n=135). CONCLUSIONS: The results suggest that serum miR-125b levels are associated with VC severity and serve as a novel predictive marker for the risk of uremia-associated calcification progression.

Impact of Self-Report and eGFR-Based Chronic Kidney Disease on the Risk of Chronic Kidney Disease-Related Complications and Geriatric Syndromes in Community-Dwelling Older Adults.

BACKGROUND/AIMS: Awareness of chronic kidney disease (CKD) has been low among affected patients, particularly the older ones. However, whether such awareness is synonymous with the presence of laboratory-diagnosed CKD among older adults is currently unclear. METHODS: We enrolled community-dwelling old adults (≥ 65 years) who received health examinations between 2013 and 2016 from a regional metropolitan hospital. Clinical information and geriatric syndromes including depression, cognitive impairment, fall, quality of life, and visual disturbance were evaluated during the medical interview. We compared the differences in clinical features between those with and without self-reported or estimated glomerular filtration rate (eGFR)-based CKD and investigated their influences and interactions on the risk of CKD complications and geriatric syndromes. RESULTS: Among the 2932 enrolled older adults (mean 73.4 ± 7 years), 93 (3%) reported that they had CKD by history, while 306 (10%) had an eGFR < 60 mL/min/1.73m2 persisted for over 3 months. The prevalence of hyperlipidemia, body mass index, waist circumference, leukocyte count, and the incidence of fall differed only between those with and without eGFR-based CKD, but not between those with and without self-reported CKD. A synergistic effect was found between self-reported and eGFR-based CKD regarding the CKD complication severity, including malnutrition (albumin), anemia (hemoglobin), dyslipidemia (serum cholesterol), and geriatric syndromes (cognitive and quality of life impairment). Multivariate regression analyses showed that self-reported CKD exhibited better predictive efficacy for lower serum albumin and hemoglobin than eGFR-based CKD, while the latter outperformed the former for predicting lower serum cholesterol and a higher risk of cognitive impairment. CONCLUSION: Among older adults, self-reported CKD may not be a surrogate for laboratory-diagnosed CKD and has an independent effect on CKD-related complications.

Diabetes mellitus, superoxide dismutase and peroxisome proliferator activated receptor gamma polymorphisms modify the outcome of end-stage renal disease patients of Han Chinese origin.

AIM: Increased oxidative stress significantly modifies the outcome of patients with diabetes mellitus (DM) and end-stage renal disease (ESRD), and is counteracted by antioxidative capacity. We aimed to investigate whether antioxidant single nucleotide polymorphisms (SNPs) influence the outcome of ESRD individuals and the influences exerted by DM, which has not been tested before. METHODS: We prospectively enrolled multi-centre ESRD patients of Han Chinese origin between 2002 and 2003, recording their antioxidant (superoxide dismutase [SOD2], glutathione peroxidase [GPX1]) and peroxisome proliferator activated receptor-γ (PPAR-γ) genotyping results, and stratified based on DM. They were followed up until 2008, with risk factors for mortality analyzed by Cox proportional hazard regression. RESULTS: We discovered that diabetic ESRD carriers of CC genotype of SOD2 exon 2 had an increased risk of mortality compared to non-diabetic ones with other genotypes (hazard ratio [HR] 4.04, P = 0.04), while GPX1 SNPs had no influence. Interactions between SOD2 and PPAR-γ SNPs regarding the mortality influence were also detected (for SOD2 CC genotype x PPAR-γ exon 6 CT genotype, HR 3.19, P = 0.008), suggesting the importance of considering a combination panel of SNPs on patient survival. CONCLUSION: This might be the largest study focusing on the relationship between antioxidant SNPs and the outcomes of diabetic ESRD patients of Han Chinese origin. More studies are needed to validate our findings.

Latent transforming growth factor binding protein 4 regulates transforming growth factor beta receptor stability.

Mutations in the gene for the latent transforming growth factor beta binding protein 4 (LTBP4) cause autosomal recessive cutis laxa type 1C. To understand the molecular disease mechanisms of this disease, we investigated the impact of LTBP4 loss on transforming growth factor beta (TGFß) signaling. Despite elevated extracellular TGFß activity, downstream signaling molecules of the TGFß pathway, including pSMAD2 and pERK, were down-regulated in LTBP4 mutant human dermal fibroblasts. In addition, TGFß receptors 1 and 2 (TGFBR1 and TGFBR2) were reduced at the protein but not at the ribonucleic acid level. Treatment with exogenous TGFß1 led to an initially rapid increase in SMAD2 phosphorylation followed by a sustained depression of phosphorylation and receptor abundance. In mutant cells TGFBR1 was co-localized with lysosomes. Treatment with a TGFBR1 kinase inhibitor, endocytosis inhibitors or a lysosome inhibitor, normalized the levels of TGFBR1 and TGFBR2. Co-immunoprecipitation demonstrated a molecular interaction between LTBP4 and TGFBR2. Knockdown of LTBP4 reduced TGFß receptor abundance and signaling in normal cells and supplementation of recombinant LTBP4 enhanced these measures in mutant cells. In a mouse model of Ltbp4 deficiency, reduced TGFß signaling and receptor levels were normalized upon TGFBR1 kinase inhibitor treatment. Our results show that LTBP4 interacts with TGFBR2 and stabilizes TGFß receptors by preventing their endocytosis and lysosomal degradation in a ligand-dependent and receptor kinase activity-dependent manner. These findings identify LTBP4 as a key molecule required for the stability of the TGFß receptor complex, and a new mechanism by which the extracellular matrix regulates cytokine receptor signaling.

Frequency of Early Predialysis Nephrology Care and Postdialysis Cardiovascular Events.

BACKGROUND: Patients with kidney failure are at a high risk for cardiovascular events. Predialysis nephrology care has been reported to improve postdialysis survival, but its effects on postdialysis major adverse cardiovascular events (MACEs) have not been comprehensively studied. STUDY DESIGN: Observational cohort study. SETTING & PARTICIPANTS: We used data from the National Health Insurance Research Database in Taiwan. Adult patients who initiated maintenance dialysis therapy in 1999 to 2010 were enrolled. PREDICTOR: We created 3 subtypes of predialysis nephrology care based on the time between the first nephrology visit and the initiation of dialysis therapy: early frequent (duration ≥ 6 months; at least 1 nephrology visit every 3 months), early infrequent (duration ≥ 6 months, <1 nephrology visit every 3 months), and late (duration < 6 months). OUTCOMES: MACE was defined using the primary diagnosis in hospitalization records of acute myocardial infarction, acute heart failure, acute stroke, or sudden death. MEASUREMENTS: We investigated the associations of different subtypes of nephrology care with postdialysis 1-year MACEs. RESULTS: Among the 60,329 eligible patients, 24,477 (40.6%) had early frequent, 12,763 (21.2%) had early infrequent, and 23,089 (38.3%) had late nephrology care. Compared to the late-nephrology-care group, the early-frequent group was associated with an ∼10% lower risk for 1-year MACEs (HR of 0.89 [95% CI, 0.82-0.96] for first MACE and relative risk of 0.91 [95% CI, 0.84-0.98] for recurrent MACEs). However, the early-infrequent-care group had similar risks for MACEs as the late group (HR of 0.95 [95% CI, 0.86-1.05] for first MACE and relative risk of 0.94 [95% CI, 0.86-1.02] for recurrent MACEs). LIMITATIONS: Lack of physical and biochemical information because of inherent limitations from administrative claims data. CONCLUSIONS: Early frequent nephrology care for 6 or more months before the initiation of long-term dialysis therapy may improve 1-year postdialysis major cardiovascular outcomes.

Frail phenotype is associated with distinct quantitative electroencephalographic findings among end-stage renal disease patients: an observational study.

BACKGROUND: Frailty is prevalent among patients with end-stage renal disease (ESRD) and is associated with an increased risk of cognitive impairment. However, apart from its influence on cognition, it is currently unknown whether frailty affects subtler cerebral function in patients with ESRD. METHODS: Patients with ESRD were prospectively enrolled, with clinical features and laboratory data recorded. The severity of frailty among these patients with ESRD was ascertained using the previously validated simple FRAIL scale, and was categorized as none-to-mild and moderate-to-severe frailty. All participants underwent quantitative electroencephalography (EEG), with band powers documented following the generation of the delta to alpha ratio (DAR) and delta/theta to alpha/beta ratio (DTABR). EEG results were then compared between groups of different levels of frailty. RESULTS: In this cohort, (mean age: 68.9 ± 10.4 years, 37% male, 3.4 ± 3 years of dialysis), 20, 60, 40, 17, and 6% patients exhibited positivity in the fatigue, resistance, ambulation, illness, and loss-of-body-weight domains, respectively, with 45.7% being none to mildly frail and 54.3% being moderately to severely frail. Those with mild frailty had a significantly higher delta power compared to those with more severe frailty, involving all topographic sites. Patients with ESRD and severe frailty had significantly lower global, left frontal, left temporo-occipital, and right temporo-occipital DAR and DTABR, except in the right frontal area, and tended to have central accentuation of alpha, beta, and theta power, and more homogeneous DTABR and DAR distribution compared to the findings in those with mild frailty. CONCLUSIONS: Frailty in patients with ESRD can have subtler neurophysiological influences, presenting as altered EEG findings, which warrant our attention.

Ferritin heavy chain mediates the protective effect of heme oxygenase-1 against oxidative stress.

The phenomenon that heme oxygenase-1 (HO-1) protects cell from injury yet its enzymatic product, iron, may facilitate generation of free radical has been long puzzling. Here we establish a functional connection between ferritin heavy chain (FHC) and HO-1. In human lupus nephritis HO-1 and FHC are colocalized within the glomeruli. In rodent anti-Thy1 (thymocyte antigen 1) induced glomerulonephritis, heme oxygenase blockade lowers the expression of FHC and accelerates mesangial cell death. Stimulation of heme oxygenase in cultured rat mesangial cell enhances its resistance to hydrogen peroxide, whereas FHC knockdown by RNA interference compromises this salutary effect. RNA interference of HO-1 makes the cell more susceptible to hydrogen peroxide, which can be rescued by forced expression of wild-type FHC but not mutants that lose the capacity of iron storage and ferroxidase activity. Phosphorylation of JunD was not sustained in these cells. Microarray analysis identifies four candidate transcriptional factors that may regulate the HO-1-induced transcription of FHC. Our results support the role of FHC in neutralizing the iron toxicity as well as mediating the protective effect of HO-1 in response to oxidative stress.