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
ObjectivesLongitudinal studies report racial disparities in prostate cancer (PCa) including greater incidence, more aggressive tumor biology, and increased cancer-specific mortality in African American (AA) men. Regret concerning primary treatment selection is underevaluated in patients with PCa. We investigated the relationships between clinicopathologic variables across racial and socioeconomic lines following robotic-assisted laparoscopic prostatectomy.Materials and methodsWe assessed treatment decisional regret using a validated questionnaire in a total of 484 white and 72 AA patients with PCa who were followed up for a median of 16.6 months post–robotic-assisted laparoscopic prostatectomy. Socioeconomic status (SES) information was aggregated from 2010 US census zip code data. Perioperative clinicopathologic characteristics and functional outcomes were compared between groups. Univariate and multivariate regression analyses were used to evaluate the influence of race, aggregate SES, and other clinical and demographic characteristics on decisional regret.ResultsThe majority (87.7%) of the population was not regretful of their decision to undergo treatment. However, a greater proportion of AA vs. white patients were regretful (20.6% vs. 11.2%, respectively; P = 0.03). AA and white men were similar on all functional, clinical, and pathologic features with the exception of younger age among AA men (56 vs. 60 y, respectively; P<0.001). Although there were significant differences in SES by race (P<0.001), regret did not differ by SES (β =?1.53; P = 0.15). Race, postoperative sexual dysfunction, pad usage, and length of hospital stay, however, were significantly associated with decisional regret.ConclusionsAA men were more regretful than white men, after adjusting for clinicopathologic characteristics and postoperative functional outcomes. 相似文献
Visacane is a sugarcane quarantine station located in the South of France, far away from sugarcane growing areas. Visacane imports up to 100 sugarcane varieties per year, using safe control and confinement measures of plants and their wastes to prevent any risk of pathogen spread outside of the facilities. Viruses hosted by the imported material are either known or unknown to cause disease in cultivated sugarcane. Poaceae viruses occurring in plants surrounding the quarantine glasshouse are currently unknown. These viruses could be considered as a source of new sugarcane infections and potentially cause new sugarcane diseases in cases of confinement barrier failure. The aim of this study was to compare the plant virome inside and outside of the quarantine station to identify potential confinement failures and risks of cross infections. Leaves from quarantined sugarcane varieties and from wild Poaceae growing near the quarantine were collected and processed by a metagenomics approach based on virion-associated nucleic acids extraction and library preparation for Illumina sequencing. While viruses belonging to the same virus genus or family were identified in the sugarcane quarantine and its surroundings, no virus species was detected in both environments. Based on the data obtained in this study, no virus movement between quarantined sugarcane and nearby grassland has occurred so far, and the confinement procedures of Visacane appear to be properly implemented. 相似文献
Genetic analysis of circulating avian influenza viruses (AIVs) in wild birds at different geographical regions during the same period could improve our knowledge about virus transmission dynamics in natural hosts, virus evolution as well as zoonotic potential. Here, we report the genetic and molecular characterization of H6N2 influenza viruses isolated from migratory birds in Turkey, Egypt, and Uganda during 2017–2018. The Egyptian and Turkish isolates were genetically closer to each other than they were to the virus isolated from Uganda. Our results also suggest that multiple reassortment events were involved in the genesis of the isolated viruses. All viruses contained molecular markers previously associated with increased replication and/or pathogenicity in mammals. The results of this study indicate that H6N2 viruses carried by migratory birds on the West Asian/East African and Mediterranean/Black Sea flyways have the potential to transmit to mammals including humans. Additionally, adaptation markers in these viruses indicate the potential risk for poultry, which also increases the possibility of human exposure to these viruses. 相似文献
AimTo investigate whether diabetes confers higher relative risks of cardiovascular events in women compared with men using contemporary data and also whether such gender-differences are dependent on age.MethodsAll patients discharged from French hospitals in 2013 with at least 5 years of follow-up and no history of major adverse cardiovascular events including heart failure (MACE-HF; heart failure, myocardial infarction, ischaemic stroke, cardiovascular death) were identified and categorized by diabetes status. Overall and age-stratified incidence rates, hazard ratios (HRs) and women-to-men ratios (WMRs) for MACE-HF leading to hospitalization were also calculated. Adjustments were then made for age and baseline characteristics according to cardiovascular risk factors and non-cardiovascular comorbidities.ResultsThe study included 2,953,816 subjects, among whom 349,928 (11.9%) had diabetes. Of those with diabetes, the absolute rate of MACE-HF was higher in men than in women (96 vs 66 per 1000 person-years); corresponding absolute rates in men and women without diabetes were 44 vs 27 per 1000 person-years. Comparing those with and without diabetes, women had a higher unadjusted HR of MACE-HF (2.45, 95% CI: 2.42–2.47) than men (2.15, 95% CI: 2.14–2.17), with an adjusted WMR of 1.13 (95% CI: 1.12–1.15). HRs of MACE-HF related to diabetes were highest in women aged around 45 years and in the youngest men and decreased with advancing age in both these groups. However, HRs were higher in women of all ages > 40 years. After adjustment, this effect was more apparent for myocardial infarction (adjusted WMR: 1.43, 95% CI: 1.38–1.48) than for either ischaemic stroke (adjusted WMR: 1.10, 95% CI: 1.07–1.14) or heart failure (adjusted WMR: 1.13, 95% CI: 1.11–1.14).ConclusionAlthough men have higher absolute risks of cardiovascular complications, the relative risks of cardiovascular complications associated with diabetes are higher in women than in men. 相似文献
