Survival improvement among patients with end-stage renal disease: trends over time for transplant recipients and wait-listed patients

Both transplant and dialysis outcomes have improved over recent years. In addition, transplantation has been shown to confer a survival benefit over maintenance dialysis. The study presented here addresses the question of whether the survival benefit of transplantation over maintenance dialysis has changed in the most recent eras. This study was based on data collected by the United States Renal Transplant Scientific Registry and the United States Renal Data System. The study sample consisted of 104,000 patients placed on the renal transplant waiting list between 1988 and 1996, of which 73,707 subsequently received renal transplants. The annualized adjusted mortality rates per 1000 patient-years were calculated by calendar year of placement on the renal transplant waiting list and for kidney transplant recipients. The resulting data were plotted, and linear curve fitting was used to estimate the slope of the change of the adjusted mortality rates by year during the period studied, 1988 to 1996. Overall annual adjusted death rates in the wait-listed patients and transplant recipients per 1000 patient-years decreased for both groups throughout the study period. From 1989 to 1996, the relative risk (RR) for patient death had decreased by 30% for transplant recipients and 23% for wait-listed patients (RR = 0.70 and 0.77; P < 0.0001 each). Slope analysis of the cause-specific mortality rates for cardiovascular disease and infection showed nearly equivalent, linear decreases for both groups. Mortality rates have improved overall and by categories of major cause of death for both renal transplant recipients and patients on the renal transplant waiting list. These favorable trends most likely represent equal advances in transplantation, dialysis, and general medical care.     

Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and beta-cell glucose responsiveness in VDF (fa/fa) Zucker rats

The incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are responsible for >50% of nutrient-stimulated insulin secretion. After being released into the circulation, GIP and GLP-1 are rapidly inactivated by the circulating enzyme dipeptidyl peptidase IV (DP IV). The use of DP IV inhibitors to enhance these insulinotropic hormonal axes has proven effective on an acute scale in both animals and humans; however, the long-term effects of these compounds have yet to be determined. Therefore, we carried out the following study: two groups of fa/fa Zucker rats (n = 6 each) were treated twice daily for 3 months with the DP IV inhibitor P32/98 (20 mg.kg(-1).day(-1), p.o.). Monthly oral glucose tolerance tests (OGTTs), performed after drug washout, revealed a progressive and sustained improvement in glucose tolerance in the treated animals. After 12 weeks of treatment, peak OGTT blood glucose values in the treated animals averaged 8.5 mmol/l less than in the controls (12.0 +/- 0.7 vs. 20.5 +/- 1.3 mmol/l, respectively). Concomitant insulin determinations showed an increased early-phase insulin response in the treated group (43% increase). Furthermore, in response to an 8.8 mmol/l glucose perfusion, pancreata from controls showed no increase in insulin secretion, whereas pancreata from treated animals exhibited a 3.2-fold rise in insulin secretion, indicating enhanced beta-cell glucose responsiveness. Also, both basal and insulin-stimulated glucose uptake were increased in soleus muscle strips from the treated group (by 20 and 50%, respectively), providing direct evidence for an improvement in peripheral insulin sensitivity. In summary, long-term DP IV inhibitor treatment was shown to cause sustained improvements in glucose tolerance, insulinemia, beta-cell glucose responsiveness, and peripheral insulin sensitivity, novel effects that provide further support for the use of DP IV inhibitors in the treatment of diabetes.     

3He-MRI-based vs. conventional determination of lung volumes in patients after unilateral lung transplantation: a new approach to regional spirometry

BACKGROUND: To use 3Helium (3He)-MRI in patients with unilateral lung grafts to assess the contributions of graft and native lung to total ventilated lung volume, and second to compare conventional measurements of intrapulmonary gas volume (spirometry, body plethysmography) with image-based volumetry of ventilated lung parenchyma visualized by hyperpolarized 3He-MRI. METHODS: With Ethics Committee approval, five patients with single lung transplantation (SLTX) for idiopathic pulmonary fibrosis (IPF) underwent both conventional pulmonary function testing (PFT) and 3He-MRI of the lung. Intrapulmonary gas volume (GV) during the inspiratory breathhold for 3He-MRI was calculated from measured functional residual capacity (corrected for supine position) and inspired tidal volume. Image-based global and regional lung volumetries (LV) were performed in three-dimensionally reconstructed 3He-MR images (corrected for the fraction of tissue and blood). RESULTS: Transplanted lungs were characterized by a homogeneous distribution of signal intensity, whereas the native lungs of the patients suffering from IPF displayed an inhomogeneous signal distribution pattern with numerous round or wedge-shaped ventilation defects. Total ventilated lung volume determined by 3He-MRI correlated well with PFT-based measurements, but with a systematic overestimation of the 3He-based lung volumetry of approximately 20%. Functioning lung grafts contributed 66+/-6% and their corresponding native IPF lungs 34+/-6% to total ventilated volume (P<0.05; mean+/-SD). CONCLUSION: 3Helium-MRI of the lung offers a novel approach to regional determination of ventilated lung volume, including its blood and tissue compartments. The advantage of this technique over computed tomography or ventilation scintigraphy is the lack of radiation exposure, and hence its repeatability. Follow up of SLTX patients with this new technique may allow the monitoring of functional and structural developments of grafted lungs with better sensitivity and specificity than PFT.     

Qualitative and quantitative evaluation of rigid and deformable motion correction algorithms using dual-energy CT images in view of application to CT perfusion measurements in abdominal organs affected by breathing motion

Objective:

To compare six different scenarios for correcting for breathing motion in abdominal dual-energy CT (DECT) perfusion measurements.

Methods:

Rigid [RR_Comm(80 kVp)] and non-rigid [NR_Comm(80 kVp)] registration of commercially available CT perfusion software, custom non-rigid registration [NR_Custom(80 kVp], demons algorithm) and a control group [CG(80 kVp)] without motion correction were evaluated using 80 kVp images. Additionally, NR_Custom was applied to dual-energy (DE)-blended [NR_Custom(DE)] and virtual non-contrast [NR_Custom(VNC)] images, yielding six evaluated scenarios. After motion correction, perfusion maps were calculated using a combined maximum slope/Patlak model. For qualitative evaluation, three blinded radiologists independently rated motion correction quality and resulting perfusion maps on a four-point scale (4 = best, 1 = worst). For quantitative evaluation, relative changes in metric values, R² and residuals of perfusion model fits were calculated.

Results:

For motion-corrected images, mean ratings differed significantly [NR_Custom(80 kVp) and NR_Custom(DE), 3.3; NR_Comm(80 kVp), 3.1; NR_Custom(VNC), 2.9; RR_Comm(80 kVp), 2.7; CG(80 kVp), 2.7; all p < 0.05], except when comparing NR_Custom(80 kVp) with NR_Custom(DE) and RR_Comm(80 kVp) with CG(80 kVp). NR_Custom(80 kVp) and NR_Custom(DE) achieved the highest reduction in metric values [NR_Custom(80 kVp), 48.5%; NR_Custom(DE), 45.6%; NR_Comm(80 kVp), 29.2%; NR_Custom(VNC), 22.8%; RR_Comm(80 kVp), 0.6%; CG(80 kVp), 0%]. Regarding perfusion maps, NR_Custom(80 kVp) and NR_Custom(DE) were rated highest [NR_Custom(80 kVp), 3.1; NR_Custom(DE), 3.0; NR_Comm(80 kVp), 2.8; NR_Custom(VNC), 2.6; CG(80 kVp), 2.5; RR_Comm(80 kVp), 2.4] and had significantly higher R² and lower residuals. Correlation between qualitative and quantitative evaluation was low to moderate.

Conclusion:

Non-rigid motion correction improves spatial alignment of the target region and fit of CT perfusion models. Using DE-blended and DE-VNC images for deformable registration offers no significant improvement.

Advances in knowledge:

Non-rigid algorithms improve the quality of abdominal CT perfusion measurements but do not benefit from DECT post processing.CT perfusion measurements allow for the assessment of blood flow in the human body by injecting the patient with an iodinated contrast agent (CA) and tracking the changes in CT values in an organ, tissue or region of interest (ROI) over time. Mathematical perfusion models relate the measured time–enhancement curves to the physiological parameters governing blood flow, such as flow rate or local blood volume. This information can be used for assessment of diseases that influence local blood flow, for example, stroke or tumours.^1–3 As a result, CT perfusion is of particular interest for the detection of isodense tumours that show a low contrast to the surrounding tissue in the arterial and venous enhancement phase of conventional CT images, e.g. pancreatic tumours.⁴While breathing motion of a patient during image acquisition has little influence on stroke assessment in the brain, CT perfusion acquisitions of the lung or abdominal organs are usually performed during breath-hold or with breathing instructions (shallow breathing) to reduce the severity of breathing motion, depending on the type of perfusion model.³ Abdominal perfusion protocols can take up to 2 min, which is much longer than the breath-hold duration to be expected from patients.⁵ Therefore, abdominal organs will always be affected by breathing-induced motion during dynamic CT acquisition, diminishing the quality of the perfusion measurements.³Motion correction can be performed by registering the CT images to a common reference image, eliminating changes in position induced by breathing motion (Figure 1). In order to achieve this, an optimization problem is solved to obtain a spatial transformation between the images by minimizing a measure for the differences in alignment. These spatial transformations are mainly classified as either rigid transformations (e.g. translation, rotation) or non-rigid transformations (e.g. deformation fields, free-form deformations).⁶Open in a separate windowFigure 1.(a) Example of the effect of breathing motion and motion correction on the spatial alignment of the region of interest (ROI) in abdominal organs, e.g. a recurrent pancreatic tumour. Note the increasing iodine enhancement within the ROI already visible at t = 4.5 s. (b) Effect of breathing motion and motion correction on the calculation of perfusion maps.The use of a motion correction algorithm can be regarded as standard in current pancreatic perfusion studies.^4,5,7 While many studies have been performed to evaluate the performance of different registration algorithms for specific problems, the effect of different registration algorithms for correction of breathing motion in abdominal CT perfusion measurements has not yet been researched in detail (Figure 1).^6,8 Previous studies suggest that the use of non-rigid registration algorithms can improve the spatial alignment of lung and liver tumours during CT perfusion studies.^9,10The performance of motion-correction algorithms might be improved by the use of dual-energy CT (DECT) image data. DECT uses two acquisitions at different energy levels (e.g. 80 and 140 kVp) to generate additional information from the differences in absorption behaviour.¹¹ This allows for the calculation of virtual non-contrast (VNC) images that subtract the enhancement caused by the CA, ideally resulting in constant CT values within the ROI over the course of the whole perfusion measurement.¹² Furthermore, linearly blended dual-energy (DE) images with a 120-kVp-equivalent weighting factor of 0.5 can provide a higher contrast-to-noise ratio than can the 80-kVp images commonly used in CT perfusion measurements and might reduce the influence of image noise on motion correction.¹³The purpose of this study was the assessment of the effectiveness of different algorithms for the correction of breathing motion in abdominal CT perfusion measurements in a clinical setting. Previous studies relying on a qualitative evaluation already reported a benefit in using non-rigid algorithms for the correction of breathing motion in liver tumours.⁹ While quantitative methods, such as percentage overlap or distance of the centre of mass, have been suggested for the evaluation of motion-correction algorithms, these methods are limited by their need for segmentation of the motion-corrected images.¹⁰In addition to the qualitative evaluation by experienced radiologists, this study provides a quantitative evaluation based on the optimization process of the motion correction and the fit of the perfusion models. Furthermore, the value of additional DECT post processing for the use in conjunction with deformable motion-correction algorithms was assessed. To our knowledge, this is the first study to provide a qualitative and quantitative evaluation of the effectiveness of different algorithms for the correction of breathing motion for CT perfusion measurements in recurring pancreatic tumours and the first study to include DECT image data for the purpose of motion correction.     

Adiponectin receptor gene expression in human skeletal muscle cells is not regulated by fibrates and thiazolidinediones

BACKGROUND: Thiazolidinediones as PPARgamma agonists and fibrates as PPARalpha agonists improve insulin sensitivity in insulin-responsive tissues. Recent data show an induction of adiponectin receptor 2 (AdipoR2) by PPARalpha and PPARgamma agonists in human macrophages. OBJECTIVE: In this study, we examined the effects of thiazolidinediones and fibrates on the expression of adiponectin receptors in human skeletal muscle cells, an important cell type in the context of insulin resistance. RESULTS AND METHODS: In vitro differentiated human myotubes treated with troglitazone or rosiglitazone (20 h) showed no significant changes in AdipoR1 and AdipoR2 mRNA expression. PPARgamma activation was controlled by determination of PPARgamma mRNA induction. Likewise, differentiated myotubes treated with Wy-14,643 or fenofibrate (20 h) revealed no significant regulation of AdipoR1 and AdipoR2 mRNA. PPARalpha activation was assessed by measuring PDHK4 mRNA expression. CONCLUSION: Induction of AdipoR gene expression in human skeletal muscle cells is not involved in the insulin-sensitizing effects of thiazolidinediones or fibrates.     

Dynamic contrast-enhanced ultrasound and transient arterial occlusion for quantification of arterial perfusion reserve in peripheral arterial disease

Objective

To quantify muscular micro-perfusion and arterial perfusion reserve in peripheral arterial disease (PAD) with dynamic contrast-enhanced ultrasound (CEUS) and transient arterial occlusion.

Materials and methods

This study had local institutional review board approval and written informed consent was obtained from all subjects. We examined the dominant lower leg of 40 PAD Fontaine stage IIb patients (mean age, 65 years) and 40 healthy volunteers (mean age, 54 years) with CEUS (7 MHz; MI, 0.28) during continuous intravenous infusion of 4.8 mL microbubbles. Transient arterial occlusion at mid-thigh level simulated physical exercise. With time–CEUS–intensity curves obtained from regions of interest within calf muscles, we derived the maximum CEUS signal after occlusion (max) and its time (t_max), slope to maximum (m), vascular response after occlusion (AUC_post), and analysed accuracy, receiver operating characteristic (ROC) curves, and correlations with ankle-brachial index (ABI) and walking distance.

Results

All parameters differed in PAD and volunteers (p < 0.014). In PAD, t_max was delayed (31.2 ± 13.6 vs. 16.7 ± 8.5 s, p < 0.0001) and negatively correlated with ankle-brachial-index (r = −0.65). m was decreased in PAD (4.3 ± 4.6 mL/s vs. 13.1 ± 8.4 mL/s, p < 0.0001) and had highest diagnostic accuracy (sensitivity/specificity, 75%/93%) for detection of diminished muscular micro-perfusion in PAD (cut-off value, m < 5∼mL/s). Discriminant analysis and ROC curves revealed m, and AUC_post as optimal parameter combination for diagnosing PAD and therefore impaired arterial perfusion reserve.

Conclusions

Dynamic CEUS with transient arterial occlusion quantifies muscular micro-perfusion and arterial perfusion reserve. The technique is accurate to diagnose PAD.     

Interaction between donor and recipient age in determining the risk of chronic renal allograft failure

OBJECTIVES: Donor age is a known risk factor for chronic allograft failure (CAF) in renal transplant recipients. We have recently shown that advanced recipient age is also a risk factor for CAF. To investigate the interaction between donor and recipient age, we analyzed 40,289 primary solitary Caucasian adult renal transplants registered at the United States Renal Data System (USRDS) from 1988 to 1997. DESIGN: CAF was defined as allograft loss beyond 6 months posttransplantation, censored for death, recurrent disease, acute rejection, thrombosis, noncompliance, infection, or technical problems. Cox proportional hazards models were used to investigate the risk of allograft loss secondary to CAF. All models were corrected for 15 covariates including donor and recipient demographics, ischemic time, and human leukocyte antigen match. Donor and recipient age were categorized, and relative risk for allograft loss of the interaction between the obtained categorical covariates was evaluated. SETTING: Retrospective data analysis using the USRDS. PARTICIPANTS: All primary Caucasian renal transplant recipients from 1988 to 1997. RESULTS: Patients aged 55 and older who received donor kidneys had a 110% increased risk of CAF (relative risk (RR) = 2.1, 95% confidence interval (CI) = 1.9-2.3, P< .001) and recipients aged 65 and older had a 90% increased risk for CAF (RR = 1.9, 95% CI = 1.61-2.1, P< .001), compared with the youngest reference groups. In addition, there was an additive and, in the long term, synergistic interaction between donor and recipient age in determining allograft loss. CONCLUSIONS: Donor and recipient age had an independent, equivalently detrimental effect on renal allograft survival. An overall additive and, in the long term (beyond 36 months posttransplant), synergistic deleterious effect on renal allograft survival was observed for the interaction of donor and recipient age.     

TRAIL mediated signaling in human mast cells: the influence of IgE-dependent activation

Background:  Mast cells activation through FcɛRI cross-linking has a pivotal role in the initiation of allergic reactions. The influence of this activation on programmed cell death of human mast cells has not yet been clarified. This study evaluates the influence of IgE-dependent activation alone and in synergy with TRAIL on the expression of molecules involved in the apoptotic signal transduction.
Methods:  Human cord blood derived mast cells (CBMC) were cultured with myeloma IgE followed by activation with anti-human IgE. The expression of proteins involved in apoptotic signal transduction was assessed by immunoblot analysis. To test the effect of activation on a pro-apoptotic stimulus, activated, IgE-treated and resting CBMC were incubated with TRAIL, or in a medium with suboptimal concentrations of stem cell factor (SCF).
Results:  In accordance with a previous study of ours, it was found that IgE-dependent activation increased TRAIL-induced caspase-8 and caspase-3 cleavage. However, it did not have a significant influence on CBMC death induced by SCF withdrawal. IgE-dependent activation increased the expression of FLIP and myeloid cell leukemia 1 (MCL-1) anti-apoptotic molecules as well as the pro-apoptotic one, BIM. In addition, a decrease in BID expression was observed. TRAIL could reverse the increase in FLIP but did not influence the upregulation of MCL-1 and of BIM.
Conclusions:  These findings suggest that IgE-dependent activation of human mast cells induces an increase in both pro-survival and pro-apoptotic molecules. We therefore hypothesized that IgE-dependent activation may regulate human mast cell apoptosis by fine-tuning anti-apoptotic and pro-apoptotic factors.