Search

Background: Diabetes mellitus is a frequent cause of the need for renal replacement therapy (RRT). Historically, RRT was started earlier in patients with diabetes, in an attempt to prevent complications of uraemia and diabetes. We did a systematic review to find support for this earlier start of dialysis in patients with versus without diabetes., Methods: The MEDLINE, EMBASE and CENTRAL databases were searched for articles about the timing of dialysis initiation in (subgroups of) patients with diabetes and CKD Stage 5., Results: A total of 340 papers were screened and 11 papers were selected to be reviewed. Only three studies showed data of at least one subgroup of patients with diabetes. Two observational studies concluded that start of dialysis with a higher estimated glomerular filtration rate (eGFR) is beneficial with regard to survival, one did not find a difference and six observational studies concluded that start of dialysis with a lower eGFR is associated with better survival in patients with diabetes. The effect of timing of initiation of dialysis did not differ between patients with versus without diabetes. Lastly, one randomized controlled trial (two papers) reported that there was no difference in survival between start at higher versus lower eGFR overall and a P-value for the interaction with diabetes of P = 0.63, indicating no difference between patients with versus without diabetes with regard to the timing of start of dialysis and subsequent mortality on dialysis., Conclusions: There is no difference between early (eGFR) and late (lower eGFR) start of RRT with regard to mortality in patients with versus without diabetes. RRT should thus be initiated based on the same criteria in all patients, irrespective of the presence or absence of diabetes., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Targeting protein stability with small molecules has emerged as an effective tool to control protein abundance in a fast, scalable and reversible manner. The technique involves tagging a protein of interest (POI) with a destabilizing domain (DD) specifically controlled by a small molecule. The successful construction of such fusion proteins may, however, be limited by functional interference of the DD epitope with electrostatic interactions required for full biological function of proteins. Another drawback of this approach is the remaining endogenous protein. Here, we combined the Cre-LoxP system with an advanced DD and generated a protein regulation system in which the loss of an endogenous protein, in our case the tumor suppressor PTEN, can be coupled directly with a conditionally fine-tunable DD-PTEN. This new system will consolidate and extend the use of DD-technology to control protein function precisely in living cells and animal models.

Background: Although many studies have suggested an association between higher uric acid (UA) and both development of chronic kidney disease (CKD) and faster decline in renal function in Stage I and II CKD, it is not clear whether this effect is consistent throughout higher CKD stages. The aim of this study was to investigate the association between baseline UA and renal outcomes in patients with established CKD (Stages III-V)., Methods: We analysed data in the Swedish Renal Registry-Chronic Kidney Disease (SRR-CKD), which is a nationwide registry of referred CKD patients. Patients with a visit between January 1(st), 2005 and December 31(st), 2011 were followed until initiation of renal replacement therapy (RRT), death, referral to primary care or end of follow-up. Decline in renal function was assessed with a linear mixed model using all estimated glomerular filtration rate (eGFR) assessments recorded during median 28 months of follow-up, adjusting for important confounders such as demographic factors, primary renal disease, age, sex, relevant medication, diet, blood pressure and body mass index., Results: There were 2466 patients with a baseline UA measurement {mean [standard deviation (SD)] of 7.81 [1.98] mg/dL}. The mean decline in renal function was -1.48 (95% CI -1.65; -1.31) mL/min/1.73 m(2) per year. The overall adjusted change in decline in renal function per unit increase in baseline UA was 0.08 (95% CI -0.01; 0.17) mL/min/1.73 m(2) per year indicating no association between higher UA levels and decline in renal function. In Stage III, IV and V CKD patients, the mean decline in renal function was -1.52 (95% CI -1.96; -1.08), -1.52 (95% CI -1.72; -1.32) and -1.19 (95% CI -1.75; -0.64) mL/min/1.73 m(2) per year, respectively. The adjusted change in the decline in renal function per unit increase in baseline UA was -0.09 (95% CI -0.30; 0.13) in Stage III CKD, 0.16 (95% CI 0.04; 0.28) in Stage IV CKD and 0.18 (95% CI -0.09; 0.45) in Stage V CKD. The overall adjusted hazard ratio for start of RRT was 0.97 (95% CI 0.93-1.02). For Stage III, IV and V CKD, it was 0.99 (95% CI 0.73-1.34), 0.97 (95% CI 0.91-1.03) and 0.99 (95% CI 0.91-1.07), respectively., Conclusion: UA is not associated with the rate of decline in renal function or time to start of RRT in Stage III, IV and/or V CKD patients., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Deep invasion of the normal surrounding tissue by primary cervical cancers is a prognostic parameter for postoperative radiotherapy and relatively worse survival. However, patients with tumor-specific immunity in the blood at the time of surgery displayed a much better disease free survival. Here we analyzed if this was due to a more tumor-rejecting immune population in the tumor., Methods: Tumor sections from a group of 58 patients with deep normal tissue-invading cervical tumors were stained for the presence of immune cells (CD45), IFNγ-producing cells (Tbet) and regulatory T cells (Foxp3) by immunohistochemistry. The slides were scanned and both the tumor area and the infiltration of the differently stained immune cells were objectively quantified using computer software., Results: We found that an increased percentage of tumor occupied by CD45+ cells was strongly associated with an enhanced tumor-infiltration by Tbet+ cells and Foxp3+ cells. Furthermore, the area occupied by CD45+ immune cells, Tbet+ cells but not Foxp3+ cells within the tumor were, in addition to the lymph node status of patients, associated with a longer disease free survival and disease specific survival. Moreover, interaction analyses between these immune parameters and lymph node status indicated an independent prognostic effect of tumor infiltrating Tbet+ cells. This was confirmed in a multivariate Cox analysis., Conclusions: The area occupied by a preferentially type I oriented CD45+ cell infiltrate forms an independent prognostic factor for recurrence-free and disease-specific survival on top of the patient's lymph node status.

Background: Patients with diabetes are at high risk of death prior to reaching end-stage renal disease, but most models predicting the risk of kidney disease do not take this competing risk into account. We aimed to compare the performance of Cox regression and competing risk models for prediction of early- and late-stage renal complications in type 2 diabetes., Methods: Patients with type 2 diabetes participating in the observational ZODIAC study were included. Prediction models for (micro)albuminuria and 50% increase in serum creatinine (SCr) were developed using Cox regression and competing risk analyses. Model performance was assessed by discrimination and calibration., Results: During a total follow-up period of 10 years, 183 out of 640 patients (28.6%) with normoalbuminuria developed (micro)albuminuria, and 22 patients (3.4%) died without developing (micro)albuminuria (i.e. experienced the competing event). Seventy-nine out of 1,143 patients (6.9%) reached the renal end point of 50% increase in SCr, while 219 (19.2%) died without developing the renal end point. Performance of the Cox and competing risk models predicting (micro)albuminuria was similar and differences in predicted risks were small. However, the Cox model increasingly overestimated the risk of increase in SCr in presence of a substantial number of competing events, while the performance of the competing risk model was quite good., Conclusions: In this study, we demonstrated that, in case of substantial numbers of competing events, it is important to account for the competing risk of death in renal risk prediction in patients with type 2 diabetes.

Background: Risk prediction models can be used to inform patients undergoing renal replacement therapy about their survival chances. Easily available predictors such as registry data are most convenient, but their predictive value may be limited. We aimed to improve a simple prediction model based on registry data by incrementally adding sets of clinical and laboratory variables., Methods: Our data set includes 1,835 Dutch patients from the Netherlands Cooperative Study on the Adequacy of Dialysis. The potential survival predictors were categorized on availability. The first category includes easily available clinical data. The second set includes laboratory values like albumin. The most laborious category contains glomerular filtration rate (GFR) and Kt/V. Missing values were substituted using multiple imputation. Within 1,225 patients, we recalibrated the registry model and subsequently added parameter sets using multivariate Cox regression analyses with backward selection. On the other 610 patients, calibration and discrimination (C-index, integrated discrimination improvement (IDI) index and net reclassification improvement (NRI) index) were assessed for all models., Results: The recalibrated registry model showed adequate calibration and discrimination (C-index=0.724). Adding easily available parameters resulted in a model with 10 predictors, with similar calibration and improved discrimination (C-index=0.784). The IDI and NRI indices confirmed this, especially for short-term survival. Adding laboratory values resulted in an alternative model with similar discrimination (C-index=0.788), and only the NRI index showed minor improvement. Adding GFR and Kt/V as candidate predictors did not result in a different model., Conclusion: A simple model based on registry data was enhanced by adding easily available clinical parameters., (© 2015 S. Karger AG, Basel.)

Cardiovascular mortality is high in ESRD, partly driven by sudden cardiac death and recurrent heart failure due to uremic cardiomyopathy. We investigated whether speckle-tracking echocardiography is superior to routine echocardiography in early detection of uremic cardiomyopathy in animal models and whether it predicts cardiovascular mortality in patients undergoing dialysis. Using speckle-tracking echocardiography in two rat models of uremic cardiomyopathy soon (4-6 weeks) after induction of kidney disease, we observed that global radial and circumferential strain parameters decreased significantly in both models compared with controls, whereas standard echocardiographic readouts, including fractional shortening and cardiac output, remained unchanged. Furthermore, strain parameters showed better correlations with histologic hallmarks of uremic cardiomyopathy. We then assessed echocardiographic and clinical characteristics in 171 dialysis patients. During the 2.5-year follow-up period, ejection fraction and various strain parameters were significant risk factors for cardiovascular mortality (primary end point) in a multivariate Cox model (ejection fraction hazard ratio [HR], 0.97 [95% confidence interval (95% CI), 0.95 to 0.99; P=0.012]; peak global longitudinal strain HR, 1.17 [95% CI, 1.07 to 1.28; P<0.001]; peak systolic and late diastolic longitudinal strain rates HRs, 4.7 [95% CI, 1.23 to 17.64; P=0.023] and 0.25 [95% CI, 0.08 to 0.79; P=0.02], respectively). Multivariate Cox regression analysis revealed circumferential early diastolic strain rate, among others, as an independent risk factor for all-cause mortality (secondary end point; HR, 0.43; 95% CI, 0.25 to 0.74; P=0.002). Together, these data support speckle tracking as a postprocessing echocardiographic technique to detect uremic cardiomyopathy and predict cardiovascular mortality in ESRD., (Copyright © 2014 by the American Society of Nephrology.)

Background: In patients with chronic kidney disease (CKD) hyperuricemia is common. Evidence that hyperuricemia might also play a causal role in vascular disease, hypertension and progression of CKD is accumulating. Therefore, we studied the association between baseline uric acid (UA) levels and the rate of decline in renal function and time until start of dialysis in pre-dialysis patients., Methods: Data from the PREPARE-2 study were used. The PREPARE-2 study is an observational prospective cohort study including incident pre-dialysis patients with CKD stages IV-V in the years between 2004 and 2011. Patients were followed for a median of 14.9 months until start of dialysis, kidney transplantation, death, or censoring. Main outcomes were the change in the rate of decline in renal function (measured as estimated glomerular filtration rate (eGFR)) estimated using linear mixed models, and time until start of dialysis estimated using Cox proportional hazards models., Results: In this analysis 131 patients were included with a baseline UA level (mean (standard deviation (SD)) of 8.0 (1.79) mg/dl) and a mean decline in renal function of -1.61 (95% confidence interval (CI), -2.01; -1.22) ml/min/1.73 m2/year. The change in decline in GFR associated with a unit increase in UA at baseline was -0.14 (95% CI -0.61;0.33, p=0.55) ml/min/1.73 m2/year. Adjusted for demography, comorbidities, diet, body mass index (BMI), blood pressure, lipids, proteinuria, diuretic and/or allopurinol usage the change in decline in eGFR did not change. The hazard ratio (HR) for starting dialysis for each mg/dl increase in UA at baseline was 1.08 (95% CI, 0.94;1.24, p=0.27). After adjustment for the same confounders the HR became significant at 1.26 (95% CI, 1.06;1.49, p=0.01), indicating an earlier start of dialysis with higher levels of UA., Conclusion: Although high UA levels are not associated with an accelerated decline in renal function, a high serum UA level in incident pre-dialysis patient is a risk factor for an earlier start of dialysis.

Background: While some prediction models have been developed for diabetic populations, prediction rules for mortality in diabetic dialysis patients are still lacking. Therefore, the objective of this study was to identify predictors for 1-year mortality in diabetic dialysis patients and use these results to develop a prediction model., Methods: Data were used from the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD), a multicenter, prospective cohort study in which incident patients with end stage renal disease (ESRD) were monitored until transplantation or death. For the present analysis, patients with DM at baseline were included. A prediction algorithm for 1-year all-cause mortality was developed through multivariate logistic regression. Candidate predictors were selected based on literature and clinical expertise. The final model was constructed through backward selection. The model's predictive performance, measured by calibration and discrimination, was assessed and internally validated through bootstrapping., Results: A total of 394 patients were available for statistical analysis; 82 (21%) patients died within one year after baseline (3 months after starting dialysis therapy). The final prediction model contained seven predictors; age, smoking, history of macrovascular complications, duration of diabetes mellitus, Karnofsky scale, serum albumin and hemoglobin level. Predictive performance was good, as shown by the c-statistic of 0.810. Internal validation showed a slightly lower, but still adequate performance. Sensitivity analyses showed stability of results., Conclusions: A prediction model containing seven predictors has been identified in order to predict 1-year mortality for diabetic incident dialysis patients. Predictive performance of the model was good. Before implementing the model in clinical practice, for example for counseling patients regarding their prognosis, external validation is necessary.

Background: There is no single model available to predict the long term survival for patients starting renal replacement therapy (RRT). The available models either predict survival on dialysis until transplantation, survival on the transplant waiting list, or survival after transplantation. The aim of this study was to develop a model that includes dialysis survival and survival after an eventual transplantation., Methods: From the Dutch renal replacement registry, patients of 16 years of age or older were included if they started RRT between 1995 and 2005, still underwent RRT at baseline (90 days after the start of RRT) and were not registered at a non-renal organ transplant waiting list (N = 13868). A prediction model of 10-year patient survival after baseline was developed through multivariate Cox regression analysis, in one half of the research group. Age at start, sex, primary renal disease (PRD) and therapy at baseline were included as possible predictors. A sensitivity analysis has been performed to determine whether listing on the transplant waiting list should be added. The predictive performance of the model was internally validated. Calibration and discrimination were computed in the other half of the research group. Another sensitivity analysis was to assess whether the outcomes differed if the model was developed and tested in two geographical regions, which were less similar than the original development and validation group. No external validation has been performed., Results: Survival probabilities were influenced by age, sex, PRD and therapy at baseline (p < 0.001). The calibration and discrimination both showed very reasonable results for the prediction model (C-index = 0.720 and calibration slope for the prognostic index = 1.025, for the 10 year survival). Adding registration on the waiting list for renal transplantation as a predictor did not improve the discriminative power of the model and was therefore not included in the model., Conclusions: With the presented prediction model, it is possible to give a reasonably accurate estimation on the survival chances of patients who start with RRT, using a limited set of easily available data.

Defects in actin dynamics affect activity-dependent modulation of synaptic transmission and neuronal plasticity, and can cause cognitive impairment. A salient candidate actin-binding protein linking synaptic dysfunction to cognitive deficits is Drebrin (DBN). However, the specific mode of how DBN is regulated at the central synapse is largely unknown. In this study we identify and characterize the interaction of the PTEN tumor suppressor with DBN. Our results demonstrate that PTEN binds DBN and that this interaction results in the dephosphorylation of a site present in the DBN C-terminus--serine 647. PTEN and pS647-DBN segregate into distinct and complimentary compartments in neurons, supporting the idea that PTEN negatively regulates DBN phosphorylation at this site. We further demonstrate that neuronal activity increases phosphorylation of DBN at S647 in hippocampal neurons in vitro and in ex vivo hippocampus slices exhibiting seizure activity, potentially by inducing rapid dissociation of the PTEN:DBN complex. Our results identify a novel mechanism by which PTEN is required to maintain DBN phosphorylation at dynamic range and signifies an unusual regulation of an actin-binding protein linked to cognitive decline and degenerative conditions at the CNS synapse.

Background: Manufacturers of energy drinks claim that their drinks can have a positive effect on cognitive performance. So far, there is little evidence that energy drinks do in fact enhance the cognitive performance of adolescents., Aim: To find out, via a series of tests, whether the manufacturers of energy drinks are justified in claiming that their drinks improve the cognitive performance of young people., Method: In a quasi-experimental design a number of young people (aged 15-18) were divided into three groups: a control group, each of whose members drank water beforehand; a placebo group whose members drank a glass of sugar-free lemonade, and an experimental group whose members drank a currently available energy drink (Megaforce). Pencil and paper tests were administered to the members of each group in order to measure attention and concentration, learning ability, memory, verbal and numerical reasoning, numerical aptitude and vocabulary., Results: No significant differences between groups were found that could solely be ascribed to the effect of energy drink., Conclusion: Given the warnings about the potential health-risks of energy drinks and the fact that no evidence was found for positive effects of energy drinks on the cognitive performance of young people, we are of the opinion that youngsters should stay away from such drinks.

Phosphatidylinositol transfer proteins (PITPs) mediate the transfer of phosphatidylinositol (PtdIns) or phosphatidylcholine (PtdCho) between two membrane compartments, thereby regulating the interface between signalling, phosphoinositide (PI) metabolism and membrane traffic. Here, we show that PITPalpha is enriched in specific areas of the postnatal and adult brain, including the hippocampus and cerebellum. Overexpression of PITPalpha, but not PITPbeta or a PITPalpha mutant deficient in binding PtdIns, enhances laminin-dependent extension of axonal processes in hippocampal neurons, whereas knockdown of PITPalpha protein by siRNA suppresses laminin and BDNF-induced axonal growth. PITPalpha-mediated axonal outgrowth is sensitive to phosphoinositide 3-kinase (PI3K) inhibition and shows dependency on the Akt/GSK-3/CRMP-2 pathway. We conclude that PITPalpha controls the polarized extension of axonal processes through the provision of PtdIns for localized PI3K-dependent signalling.

Three boys, aged 5, 11 and 14 years, were admitted due to vomiting, fatigue and dehydration, and a 10-year-old boy was admitted due to circulatory and respiratory insufficiency. Two had Addison's disease, one had a late presentation of congenital adrenal hypoplasia due to a DAX-1 mutation and in one adrenal insufficiency was the first manifestation ofadrenoleukodystrophia. The boys recovered after treatment. It is important to recognise the symptoms of adrenal insufficiency, because treatment can be life-saving. After the initial diagnosis the underlying pathology should be sought.

Adrenalectomy enhances apoptosis in the rat dentate gyrus and concurrently decreases the field response of dentate cells to perforant path stimulation. Recent data showed that calcium current amplitude is increased 1 day prior to the appearance of apoptotic cells, pointing to calcium as a risk factor for the onset of apoptosis. We here tested if in vivo administration of nimodipine-thus presumably reducing dentate calcium influx through L type calcium channels-prevents the appearance of apoptotic cells and the change in field responses after adrenalectomy. It was found that nimodipine does not largely alter the number of animals with apoptosis nor the average number of apoptotic cells in the tip of the suprapyramidal blade of the dentate gyrus. After nimodipine treatment, field responses in the dentate gyrus of adrenalectomized rats were comparable to responses in adrenally intact rats. However, this was due to a reduction of the field response in slices from adrenally intact rats, rather than a prevention of synaptic impairment in adrenalectomized rats. The data clearly indicates that in vivo nimodipine treatment is insufficient to prevent apoptosis and synaptic impairment after adrenalectomy., (Copyright 2002 Wiley-Liss, Inc.)

The potency of each batch of inactivated Newcastle disease virus (NDV) vaccine is measured in either a vaccination-serology or a vaccination-challenge experiment. We have developed an antigen quantification assay as an in vitro alternative for these currently prescribed in vivo potency assays. The in vitro assay consists of extraction of the viral antigens from the oil emulsion vaccines by isopropylmyristate, followed by quantification of the NDV HN-antigen in an ELISA. The analysis of 20 inactivated vaccines, representing the most common NDV-vaccines in Western Europe, indicated that large differences in antigen content exist between these vaccines. A comparison of the antigen content with the serological response after vaccination with 1/50 vaccine dose demonstrated that a reliable estimate of the potency can be made, based on the HN-antigen content of the vaccine. We therefore present our antigen quantification assay for NDV as a candidate in vitro potency assay. An international feasibility and validation study will be needed to prove the suitability and reliability of this candidate in vitro potency assay for inactivated NDV vaccines.

Recent studies showed that corticosterone and NMDA receptor activation suppress cell turn-over in the dentate gyrus through a common pathway, the NMDA receptor acting downstream of the corticosteroids. The present data show that in the absence of corticosteroids but not of NMDA receptor activation synaptic responses of dentate cells are reduced. The reduced synaptic responsiveness in the absence of corticosterone is therefore probably not caused by changes in cell turn-over.