GFR decline in patients with CKD has been widely approximated using linear models, but this linearity assumption is not well validated. We conducted a matched case-control study in children from the Chronic Kidney Disease in Children (CKiD) cohort ages 1–16 years with mild to moderate CKD to assess whether GFR decline follows a nonlinear trajectory as CKD approaches ESRD. Children (n=125) who initiated RRT (cases) during follow-up were individually matched by CKD stage at baseline and glomerular/nonglomerular diagnosis with children (n=125) who remained RRT-free when the corresponding case initiated RRT (controls). GFR trajectories were compared using log-linear and piecewise log-linear mixed effects models adjusted for baseline characteristics. From study entry to 18 months before RRT, GFR declined 7% faster among cases compared with controls. However, GFR declined 26% faster among cases compared with controls (P<0.001) during the 18 months before RRT. Nonlinearity in the rate of kidney function loss, which was shown in this cohort, may preclude accurate clinical prediction of the timing of RRT and adequate patient preparation. This study should prompt the characterization of predictive factors that may contribute to an acceleration of kidney function decline.GFR is a key measurement of kidney function, and the degree of GFR decline over time is a reflection of the severity of CKD progression. GFR decline has been approximated as linear or log-linear in most analyses of progression, an assumption that has been consistent with available data.1–4 However, many studies rely on relatively short follow-up periods and few repeated measures. Given the convenience of assuming a linear GFR trajectory, which results from the ease of modeling and interpreting linear slopes, few studies have sought to validate the linearity assumption and explore the possibility of nonlinear GFR decline. However, nonlinearity in GFR decline has been observed in some epidemiologic studies,5–7 and the implications on the risk for adverse outcomes have generated interest.8 A CKD cohort study in France found that about one half of its patients experienced nonlinear GFR decline during the last year before dialysis.5 A study by Li et al.9 used a flexible approach to model nonlinearity in GFR trajectories. Li et al.9 found evidence of nonlinear GFR trajectory behavior in adult patients with CKD, and furthermore, the probability of having nonlinear features in an individual trajectory was associated with known risk factors for CKD progression. O’Hare et al.10 found several distinct nonlinear patterns of GFR decline in the 2 years before dialysis initiation in Veterans Affairs patients.Clinical strategies and subsequent patient response to care could potentially benefit from new insights into the variable paths of progression in patients with CKD.10,11 The question of whether characterizing the nonlinearity in the GFR trajectory can assist the identification of risk groups for outcomes, such as ESRD, remains unexplored. The implications on future outcomes of an increased rate of GFR decline could inform clinical decisions about screening frequencies, treatment, or preparation for RRT.The Chronic Kidney Disease in Children (CKiD) study is an ongoing cohort study of children with CKD who, at baseline, had an eGFR between 30 and 90 ml/min per 1.73 m3 and were ages 1–16 years. An end point of the study is RRT defined as transplant or dialysis. To determine whether trajectories of GFR accelerate before RRT, we nested a case-control study, in which cases were children observed to have received RRT and controls were children with CKD who remained RRT-free at the time when the corresponding case initiated RRT.There were 147 children who experienced RRT during follow-up. Each case was matched individually to an eligible control at the time of the case occurrence. The matching factors included baseline CKD stage, glomerular/nonglomerular diagnosis, and, through design, the amount of follow-up time from study entry. Matching was done without replacement, and 22 cases were excluded from the analyses, because no appropriate control was available. We used a random sequence to determine the order of matching. The analysis was, thus, based on 125 matched case-control pairs. Demographic and clinical characteristics of cases and controls at baseline are shown in
Open in a separate windowMedian (interquartile range) unless otherwise indicated.aBaseline GFR and glomerular/nonglomerular diagnosis were matching factors.We compared the GFR trajectories using log-linear and piecewise log-linear mixed effects models, with the piecewise model specified to allow a change of the GFR slope at 18 months before RRT. Models were adjusted for baseline characteristics, including age, race, sex, and proteinuria status. and33 show the adjusted results from the mixed effects model analyses. The Akaike Information Criterion indicated that the piecewise log-linear model (including a spline or changing slope at 18 months before RRT) was a better fit to the data than the log-linear model that assumed a single slope across the entire period of observation. The GFR of cases declined at an adjusted rate of 6.8% per year (P <0.001) during the time before the spline in the earlier period of observation and 32.4% per year (P <0.001) after the spline within 18 months of RRT. The GFR of controls did not change significantly (P=1.00) before the spline and declined at an adjusted rate of 9.0% (P <0.001) after the spline. Although the rates of GFR decline comparing cases with controls differed by only 7% before the spline, the GFR of cases declined 26% faster (P <0.001) compared with controls within 18 months of RRT, suggesting an acceleration in the GFR decline during this period in the case group. This acceleration, which was quantified by the piecewise log-linear mixed effects model, could be clearly seen from the data and nonparametric smooth fits (Figure 1). The variability around the piecewise log-linear fit was assessed by the root mean square error (RMSE) and found to be similar between cases and controls (RMSE for controls=0.303; RMSE for cases=0.303), indicating an equally good fit. When a single slope was fit to the data, the GFR decline rate for cases was overestimated before the spline and considerably underestimated within 18 months of RRT. To assess whether the acceleration in decline was a function of the log scale, models were rerun with GFR in the natural scale. The results showed similar nonlinear patterns but a poorer model fit to the data.
Table 2.
The adjusted expected percent GFR change rates in the log-linear mixed effects model
Case Group
Adjusted % GFR Change per Year
SEM (%)
P Value
Controls
−3.2
1.2
0.01
Cases
−18.2
0.9
<0.001
Cases-controls
−15.5
1.3
<0.001
AIC
260.78
Open in a separate windowParameter estimates from the models are provided in Supplemental Appendix II. All results were adjusted for baseline characteristics, including age, race, sex, and proteinuria status. AIC, Akaike Information Criterion.
Table 3.
The adjusted expected percent GFR change rates in the piecewise log-linear mixed effects model
Case Group
Before 18 mo before RRT of Cases
After 18 mo before RRT of Cases
Difference between Early and Late Slopesa
Adjusted % GFR Change per Year
SEM (%)
P Value
Adjusted % GFR Change per Year
SEM (%)
P Value
Adjusted % GFR Change per Year
SEM (%)
P Value
Controls
0.3
1.5
0.87
−9.0
2.5
<0.001
9.2
3.3
0.01
Cases
−6.8
1.3
<0.001
−32.4
1.3
<0.001
27.4
2.0
<0.001
Cases-controls
−7.0
1.9
<0.001
−25.7
2.5
<0.001
AIC
149.14
Open in a separate windowParameter estimates from the models are provided in Supplemental Appendix II. All results were adjusted for baseline characteristics, including age, race, sex, and proteinuria status.aDifference resulting from the piecewise linear mixed effects model estimated in the log scale and then exponentiated.Open in a separate windowFigure 1.Nonlinear GFR decline before RRT can be approximated with a piece-wise log-linear model. A and B show the smooth fit of log GFR over time for cases of RRT and matched controls anchoring at the RRT onset time of cases. C and D show the fit from the adjusted log-linear and adjusted piecewise log-linear mixed effects models for cases of RRT and matched controls anchoring at the RRT onset time of cases. Models were adjusted for baseline characteristics including age, race, sex, and proteinuria status.Our results show that, although linear or log-linear GFR decline is a convenient assumption for longitudinal studies of CKD progression, individuals experience periods of accelerated decline. Li et al.9 showed that patients in the African American Study of Kidney Disease and Hypertension experienced a variety of nonlinear progression patterns. O’Hare et al.10 classified CKD patients who progressed to dialysis into four GFR trajectory categories and found evidence that patients with mild to moderate CKD experienced more rapid renal function deterioration in the 2 years before reaching long-term dialysis. In the current study assessing progression in children with CKD, we found similar results, indicating that RRT events are preceded by a period of accelerated decline in GFR. It is likely that this period of precipitous loss in kidney function is a key factor in the determination of the timing of RRT. An acceleration of GFR decline may be a primary feature of a worsening clinical profile that prompts a clinician to initiate dialysis or transplant. The question arises as to what contributes to accelerated kidney function loss. A primary epidemiologic challenge is to find predictors that antecede the acceleration and are amenable to intervention to prevent or delay such accelerated loss and RRT. Clearly, these results and the questions that they raise speak to a need for additional investigations of CKD progression in various populations, with care taken to appropriately characterize changing levels of factors that are known predictors of CKD progression. The timing of potential insults to the kidney (e.g., loss of control of BP) may hold important information concerning the patterns of CKD progression and nonprogression. O’Hare et al.10 found that rates of recommended pre-ESRD care were lower for those patients experiencing the most rapid progression before dialysis initiation. Ambrogi et al.5 suggested that nonlinear patterns in GFR decline might create difficulty in estimating the timing of dialysis.These results may also highlight the coarseness of current methods for assessing the impact of risk factors on CKD progression, which mainly rely on the assumption of linear decline in kidney function. Analyses assuming linear decline average over nonlinear patterns that speak to the true nature of the exposure–outcome relationships. More sensitive analyses may be needed to characterize the heterogeneity in the patterns that describe CKD progression and assess the impact of often changing values of the exposure. Improvements in how we characterize patterns of progression could lead to new approaches to clinical care, because accelerations in kidney function loss may complicate the timing of RRT and pre-ESRD care.7,10There are several strengths of this study. We drew from a well characterized cohort of children with CKD with directly measured GFR at the first two annual study visits and all even visits thereafter. The CKiD study also has an internally derived estimating equation for GFR to capture kidney function in odd visit years of the study, thereby providing regular GFR assessments for characterizing nonlinear patterns of GFR decline. The CKiD study has longitudinal data for up to 6 years of follow-up, and the multicenter setting with 43 clinical sites provides a sample of children highly representative of the pediatric CKD population in care in the United States. By adopting the case-control design, we were able to compare the nonlinearity of the GFR trajectory before RRT with the expected trajectory in comparable children who had not yet experienced RRT.There are also notable limitations to the current analysis. There were only 125 case-control pairs, and our GFR assessments were annual, limiting the degree to which heterogeneity in progression to RRT could be assessed among the case group. As has been reported previously, there is likely variation in GFR patterns before RRT.10 However, what is clear from the current study is that, on average, children approaching RRT experience acceleration in their loss of kidney function. Another consideration is the assumption of a break in linearity at 18 months before RRT, which provided sufficient data before and after the spline for our analyses but is an oversimplification of what is likely a more prolonged period of acceleration in GFR decline. However, our choice of 18 months before RRT to examine changes in the rate of GFR decline is consistent with other studies that have noted similar rapid declines in kidney function within 2 years of dialysis.10,12 Finally, it should be noted that, although cases and controls were matched, the models in and33 did not cluster on the matched pairs. Our final model provided practically identical results to a model including an additional random effect for case-control pair, and it had modestly higher precision. 相似文献
Background and PurposeMany young people consume ecstasy as a recreational drug and often in combination with cannabis. In this study, we aimed to mimic human consumption patterns and investigated, in male and female animals, the long-term effects of Δ9-tetrahydrocannabinol (THC) and 3,4-methylenedioxymethamphetamine (MDMA) on diverse neuroinflammation and neurotoxic markers.Experimental ApproachMale and female Wistar rats were chronically treated with increasing doses of THC and/or MDMA during adolescence. The effects of THC and/or MDMA on glial reactivity and on serotoninergic and cannabinoid systems were assessed by immunohistochemistry in the hippocampus and parietal cortex.Key ResultsTHC increased the area staining for glial fibrilar acidic protein in both sexes. In males, both drugs, either separately or in combination, increased the proportion of reactive microglia cells [ionized calcium binding adaptor molecule 1 (Iba-1)]. In contrast, in females, each drug, administered alone, decreased of this proportion, whereas the combination of both drugs resulted in a ‘normalization’ to control values. In males, MDMA reduced the number of SERT positive fibres, THC induced the opposite effect and the group receiving both drugs did not significantly differ from the controls. In females, MDMA reduced the number of SERT positive fibres and the combination of both drugs counteracted this effect. THC also reduced immunostaining for CB1 receptors in females and this effect was aggravated by the combination with MDMA.Conclusions and ImplicationsAdolescent exposure of rats to THC and/or MDMA induced long-term, sex-dependent neurochemical and glial alterations, and revealed interactions between the two drugs.Linked ArticlesThis article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6相似文献
This paper demonstrates the use of peridynamics and discrete multiphysics to assess micro crack formation and propagation in asphalt at low temperatures and under freezing conditions. Three scenarios are investigated: (a) asphalt without air voids under compressive load, (b) asphalt with air voids and (c) voids filled with freezing water. The first two are computed with Peridynamics, the third with peridynamics combined with discrete multiphysics. The results show that the presence of voids changes the way cracks propagate in the material. In asphalt without voids, cracks tend to propagate at the interface between the mastic and the aggregate. In the presence of voids, they ‘jump’ from one void to the closest void. Water expansion is modelled by coupling Peridynamics with repulsive forces in the context of Discrete Multiphysics. Freezing water expands against the voids’ internal surface, building tension in the material. A network of cracks forms in the asphalt, weakening its mechanical properties. The proposed methodology provides a computational tool for generating samples of ‘digital asphalt’ that can be tested to assess the asphalt properties under different operating conditions. 相似文献
ObjectiveTo characterize diabetes care across healthcare facilities in six Peruvian regions.MethodsCross-sectional study of patients with type 2 diabetes mellitus (T2DM), ranging from primary care facilities to hospital-based facilities, in six Peruvian regions. Data was collected by health staff trained between 2012 and 2016. We studied six diabetes care outcomes and four adequate diabetes care outcomes considering the healthcare facility as the exposure of interest. We estimated prevalence ratios (PR) and their 95% confidence intervals (95% CI) using Poisson regression with robust variance.ResultsData from 8879 patients with T2DM, mean age 59.1 years (SD ± 12.2), 53.6% males, was analyzed. Of these, 8096 (91.2%) were treated at primary care facilities. The proportions of patients who had HbA1c, LDL-c, and creatinine/microalbumin test performed increased with the setting of the healthcare facility. Overall, 39%–56% of patients had an adequate HbA1c control, being higher in hospital-based facilities with specialists in comparison to primary care facilities.ConclusionsWe observed that the higher the setting of the facility, the higher the rate of the assessed diabetes care outcomes and adequate diabetes care for four of the six targets (fasting glucose, HbA1c, LDL-c and creatinine or microalbumin) and for three of the four targets (glucose≤130 mg/dL, HbA1c ≤7%(53 mmol/mol) and LDL-c <100 mg/dL), respectively. Substantial gaps were observed at the primary care facilities, calling for the strengthening of diabetes care. 相似文献
Herein, the influence of the substrate in the formation of zirconium oxide monolayer, from an aqueous hexafluorozirconic acid solution, by chemical conversion and by electro-assisted deposition, has been approached. The nanoscale dimensions of the ZrO2 film is affected by the substrate nature and roughness. This study evidenced that the mechanism of Zr-EAD is dependent on the potential applied and on the substrate composition, whereas conversion coating is uniquely dependent on the adsorption reaction time. The zirconium oxide based nanofilms were more homogenous in AA2024 substrates if compared to pure Al grade (AA1100). It was justified by the high content of Cu alloying element present in the grain boundaries of the latter. Such intermetallic active sites favor the obtaining of ZrO2 films, as demonstrated by XPS and AFM results. From a mechanistic point of view, the electrochemical reactions take place simultaneously with the conventional chemical conversion process driven by ions diffusion. Such findings will bring new perspectives for the generation of controlled oxide coatings in modified electrodes used, as for example, in the construction of battery cells; in automotive and in aerospace industries, to replace micrometric layers of zinc phosphate by light-weight zirconium oxide nanometric ones. This study is particularly addressed for the reduction of industrial waste by applying green bath solutions without the need of auxiliary compounds and using lightweight ceramic materials. 相似文献
We report a transfusion trial of platelets photochemically treated for pathogen inactivation using the synthetic psoralen amotosalen HCl. Patients with thrombocytopenia were randomly assigned to receive either photochemically treated (PCT) or conventional (control) platelets for up to 28 days. The primary end point was the proportion of patients with World Health Organization (WHO) grade 2 bleeding during the period of platelet support. A total of 645 patients (318 PCT and 327 control) were evaluated. The primary end point, the incidence of grade 2 bleeding (58.5% PCT versus 57.5% control), and the secondary end point, the incidence of grade 3 or 4 bleeding (4.1% PCT versus 6.1% control), were equivalent between the 2 groups (P =.001 by noninferiority). The mean 1-hour posttransfusion platelet corrected count increment (CCI) (11.1 x 10(3) PCT versus 16.0 x 10(3) control), average number of days to next platelet transfusion (1.9 PCT versus 2.4 control), and number of platelet transfusions (8.4 PCT versus 6.2 control) were different (P <.001). Transfusion reactions were fewer following PCT platelets (3.0% PCT versus 4.4% control; P =.02). The incidence of grade 2 bleeding was equivalent for PCT and conventional platelets, although posttransfusion platelet count increments and days to next transfusion were decreased for PCT compared with conventional platelets. 相似文献
Although nonmyeloablative conditioning regimen transplantations (NMTs) induce engraftment of allogeneic stem cells with a low spectrum of toxicity, graft-versus-host disease (GVHD) remains a significant cause of morbidity and mortality. In vivo T-cell depletion, using alemtuzumab, has been shown to reduce the incidence of GVHD. However, this type of maneuver, although reducing GVHD, may have an adverse impact on disease response, because NMTs exhibit their antitumor activity by relying on a graft-versus-malignancy effect. To explore the efficacy of alemtuzumab compared with methotrexate (MTX) for GVHD prophylaxis, we have compared the results in 129 recipients of a sibling NMT enrolled in 2 prospective studies for chronic lymphoproliferative disorders. Both NMTs were based on the same combination of fludarabine and melphalan, but the United Kingdom regimen (group A) used cyclosporin A plus alemtuzumab, whereas the Spanish regimen (group B) used cyclosporin A plus MTX for GVHD prophylaxis. Patients receiving alemtuzumab had a higher incidence of cytomegalovirus (CMV) reactivation (85% versus 24%, P <.001) and a significantly lower incidence of acute GVHD (21.7% versus 45.1%, P =.006) and chronic GVHD (5% versus 66.7%, P <.001). Twenty-one percent of patients in group A and 67.5% in group B had complete or partial responses 3 months after transplantation (P <.001). Eighteen patients in group A received donor lymphocyte infusions (DLIs) to achieve disease control. At last follow-up there was no difference in disease status between the groups with 71% versus 67.5% (P =.43) of patients showing complete or partial responses in groups A and B, respectively. No significant differences were observed in event-free or overall survival between the 2 groups. In conclusion, alemtuzumab significantly reduced GVHD but its use was associated with a higher incidence of CMV reactivation. Patients receiving alemtuzumab often required DLIs to achieve similar tumor control but the incidence of GVHD was not significantly increased after DLI. 相似文献
To determine the role of anxiety and depression on the incidence of cardiovascular events (CVE) in a Catalonian population with metabolic syndrome (MetS) over a five-year follow-up according to the number/type of MetS criteria.
Methods
Prospective study to determine the incidence of CVE according to the presence of anxiety and depression disorders among individuals with different combinations of clinical traits of the MetS. Setting: Primary Care, Catalonia (Spain). Subjects: 35–75 years old fulfilling MetS criteria without CVE at the initiation of follow-up (2009). We studied 16 MetS phenotypes [NCEP-ATPIII criteria] based on the presence of depression/anxiety. The primary endpoint was the incidence of CVE at five years.
Results
We analyzed 401,743 people with MetS (17.2% of the population); 8.7% had depression, 16.0% anxiety and 3.8% both. 14.5% consumed antidepressants and 20.8% tranquilizers. At the 5-year follow-up, the incidence of CVE was 5.5%, being 6.4% in men and 4.4% in women. On comparing individuals with and without depression the incidence of CVE was 6.7% vs. 5.3%, respectively (p < 0.01), being 5.5% in both groups in relation to anxiety.
Conclusion
Depression and anxiety play a role in the poor prognosis of patients with MetS. In Catalonia, the two predominant MetS phenotypes do not include obesity as a criterion. 相似文献
