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
While human epidermal growth factor receptor 2 (HER2) overexpression is an adverse breast cancer prognostic factor, it is unclear whether there are differences in outcomes between types of local treatment in this population. This retrospective study examined locoregional recurrence and survival in women with node-negative, HER2+ breast cancer treated with breast-conserving therapy (BCT) versus mastectomy.
Methods
Subjects were 748 patients with pT1–2, N0, M0 HER2+ breast cancer, treated with BCT (n = 422) or mastectomy (n = 326). Trastuzumab was used in 54 % of subjects. The 5-year Kaplan–Meier locoregional recurrence free survival (LRRFS), breast cancer specific survival (BCSS), and overall survival (OS) were compared between cohorts treated with BCT versus mastectomy. Subgroup analyses of LRR and survival were performed separately among patients treated with BCT or mastectomy to examine the effect of trastuzumab on outcomes in each group.
Results
Median follow-up was 4.4 years. Patients treated with mastectomy had higher proportions of grade 3 histology (69 vs 60 %, p = 0.004) and lower rates of hormone therapy (51 vs 64 %, p < 0.001) and trastuzumab therapy (50 vs 57 %, p = 0.04). The 5-year outcomes in women treated with BCT compared with mastectomy were: LRRFS 98.0 versus 98.3 % (p = 0.88), BCSS 97.2 versus 96.1 % (p = 0.70), and OS 95.5 versus 93.4 % (p = 0.19). Trastuzumab was associated with similar LRRFS and improved OS in both local treatment groups.
Conclusions
BCT is safe in the population of women with pT1–2, N0, HER2+ breast cancer, providing high rates of locoregional control and survival equivalent to mastectomy. Trastuzumab was associated with improved survival in both groups. 相似文献
The surgical indications for symptomatic rectocele are undefined, and surgery has high recurrence rates. We implemented magnetic resonance imaging defecography (MRID) to determine if utilizing strict inclusion criteria for rectocele repair improves outcomes.
Methods
Patients with obstructive defecation syndrome (ODS) who underwent dynamic MRID were evaluated. Indications for surgical repair were defecation requiring manual assistance and the following MRID results: anterior defect >2 cm, incomplete evacuation, and the absence of perineal descent. Primary outcomes were the change in quality of life (QOL) scores and recurrence.
Results
From 2006 to 2013, 143 patients who presented with ODS underwent MRID. Seventeen patients met the criteria for repair. Recurrence was low (5.8%) with a median follow-up of 23 months, QOL scores improved from 57.3 to 76.5 (P = .041).
Conclusions
A minority of patients (12%) with ODS met the above criteria for rectocele repair. Patients who underwent repair had a significant improvement in QOL and low recurrence rate. 相似文献
Animal models have demonstrated that CD36 facilitates cell membrane free fatty acid (FFA) transport, but its role in human metabolism is not well understood. We measured heart, liver, adipose (three depots), and muscle (truncal postural and thigh locomotive) FFA uptake using [11C]palmitate positron emission tomography (PET) scans in a family of five carrying the Pro90Ser CD36 mutation (2 homozygotes had no CD36) and matched control volunteers. PET scans were done under conditions of suppressed and slightly increased palmitate concentrations. During suppressed palmitate conditions, muscle and adipose palmitate uptake were markedly reduced in homozygotes but not heterozygotes for the Pro90Ser CD36 mutation, whereas when palmitate concentration was slightly increased, uptake in muscle and adipose did not differ between control subjects and homozygous family members. Hepatic FFA uptake was similar in all participants regardless of palmitate concentrations, whereas myocardial FFA uptake was diminished in the Pro90Ser homozygotes during both suppressed and increased palmitate conditions. We conclude that CD36 1) facilitates FFA transport into muscle and adipose tissue in humans when extracellular concentrations are reduced but not when they are modestly elevated, 2) is not rate limiting for hepatic FFA uptake, and 3) is needed for normal cardiac FFA uptake over a range of FFA concentrations from low to slightly elevated. 相似文献
Operative fixation of displaced, mid-shaft clavicle fractures has become an increasingly common practice. With this emerging trend, data describing patient outcomes with longer follow-up are necessary.
Patients and Methods
We retrospectively reviewed the medical records of subjects treated with plate fixation for displaced mid-shaft clavicle fractures from 2003 to 2009 at a Level I trauma hospital. All subjects were greater than 12 months post-index surgery. Treatment involved ORIF with either a low-contact dynamic compression plate (LCDC) or a contoured plate (pre-contoured or pelvic reconstruction plate). Our primary outcome was reoperation for any indication.
Results
143 subjects were included. The mean age was 36 ± 14 years and the mean time to reoperation or chart review was 33 months. Contoured plates were used in 64% of cases and LCDC plates were used in the remaining subjects. Twenty-nine subjects (20%) underwent reoperation: 23.5% of subjects treated with LCDC plates and 18.5% of subjects treated with contoured plates (p = 0.52). Indications for reoperation included implant irritation (n = 25), implant failure (n = 2), and non-union (n = 2). There was near statistically significant association with reoperation and female gender (p = 0.05) but no association between reoperation and age (p = 0.14), fracture class (p = 0.53), plate type (p = 0.49), or plate location (p = 0.93). The mean QuickDASH score for the population surveyed was 8.8 (5.5–12.1; 95% CI) with near statistically significant and clinically relevant difference between those considering reoperation and those not 22.3 (8.6–36.0; 95% CI) versus 6.7 (3.6–9.8; 95% CI).
Conclusions
This study represents a large series of displaced clavicle fractures treated with open reduction and plate fixation. Reoperation following plate fixation is relatively common, but primarily due to implant irritation. No difference in reoperation rates between plate types or location could be detected in our current sample size. Also, excellent functional outcomes continue to be observed several years after clavicle fracture fixation. 相似文献
Branding and advertising have a powerful effect on both familiarity and preference for products, yet no neuroimaging studies have examined neural response to logos in children. Food advertising is particularly pervasive and effective in manipulating choices in children. The purpose of this study was to examine how healthy children’s brains respond to common food and other logos. A pilot validation study was first conducted with 32 children to select the most culturally familiar logos, and to match food and non-food logos on valence and intensity. A new sample of 17 healthy weight children were then scanned using functional magnetic resonance imaging. Food logos compared to baseline were associated with increased activation in orbitofrontal cortex and inferior prefrontal cortex. Compared to non-food logos, food logos elicited increased activation in posterior cingulate cortex. Results confirmed that food logos activate some brain regions in children known to be associated with motivation. This marks the first study in children to examine brain responses to culturally familiar logos. Considering the pervasiveness of advertising, research should further investigate how children respond at the neural level to marketing. 相似文献
