Background
Assessing bias (estimated – measured) is key to evaluating glomerular filtration rate (GFR). Stratification by subgroups can indicate where equations perform differently. However, there is ...a fallacy in the assessment of two instruments (e.g., eGFR and mGFR) when stratifying on the level of only one of those instruments. Here, we present statistical aspects of the problem and a solution for GFR stratification along with an empirical investigation using data from the CKiD study.
Methods
Compared and contrasted biases (eGFR relative to mGFR) with 95% confidence intervals within strata of mGFR only, eGFR only, and the average of mGFR and eGFR using data from the Chronic Kidney Disease in Children (CKiD) study.
Results
A total of 304 participants contributed 843 GFR studies with a mean mGFR of 48.46 (SD = 22.72) and mean eGFR of 48.67 (SD = 22.32) and correlation of 0.904. Despite strong agreement, eGFR significantly overestimated mGFR when mGFR < 30 (+ 6.2%; 95%CI + 2.9%, + 9.7%) and significantly underestimated when mGFR > 90 (–12.2%; 95%CI − 17.3%, − 7.0%). Significant biases in opposite direction were present when stratifying by eGFR only. In contrast, when stratifying by the average of eGFR and mGFR, biases were not significant (+ 1.3% and − 1.0%, respectively) congruent with strong agreement.
Conclusions
Stratifying by either mGFR or eGFR only to assess eGFR biases is ubiquitous but can lead to inappropriate inference due to intrinsic statistical issues that we characterize and empirically illustrate using data from the CKiD study. Using the average of eGFR and mGFR is recommended for valid inferences in evaluations of eGFR biases.
Graphical Abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
Using data (2655 observations from 928 participants) from the Chronic Kidney Disease in Children Study, we developed and internally validated new glomerular filtration rate estimating equations for ...clinical use in children and young adults: two forms of K × heigh(ht) / serum creatinine(sCr) and two forms of K × 1 / cystatin C(cysC). For each marker, one equation used a sex-dependent K; in the other, K is sex-and age-dependent. Glomerular filtration rate (GFR) was measured directly by plasma iohexol disappearance. The equations using ht⁄sCr had sex-specific constants of 41.8 for males and 37.6 for females. In the age- dependent models, K increased monotonically for children 1-18 years old and was constant for young adults 18-25 years. For males, K ranged from 35.7 for one-year-olds to 50.8 for those 18 and older. For females, the values of K ranged from 33.1 to 41.4. Constant K values for cystatin-C equations were 81.9 for males and 74.9 for females. With age-dependency, K varied non-monotonically with the highest values at age 15 for males (K of 87.2) and 12 years for females (K of 79.9). Use of an age-dependent K with ht/sCr models reduced average bias, notably in young children and young adults; age-dependent cystatin-C models produced similar agreement to using a constant K in children under 18 years, but reduced bias in young adults. These age-dependent proposed equations were evaluated alongside estimated GFRs from 11 other published equations for pediatrics and young adults. Only our proposed equations yielded non- significant bias and within 30% accuracy values greater than 85% in both the pediatric and young adult subpopulations.
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Quality control in longitudinal cohort studies is critical for valid epidemiologic inference. Conditional studentized residuals (CSRs) derived from linear mixed effects models offer efficient ...individual-specific quality control. We present the utility of CSRs for outlier detection in an applied example using data from the Chronic Kidney Disease in Children cohort.
Longitudinal linear mixed effects models with glomerular filtration rate (GFR) as the outcome were fit for observations prior to kidney replacement therapy, stratified by nonglomerular or glomerular diagnosis, and for a subset after receiving a kidney transplant. For each model, CSRs were calculated and values ≥±5 were considered potential outliers for further investigation.
A total of 1096 participants contributed 6881 annual measures of GFR across the two diagnostic groups and after transplant. In all models, the fixed effects captured progressive GFR decline. CSRs provided measures of individual-level deviations from the modeled trajectories (random + fixed effects) and were easily visualized in longitudinal plots. A total of 38 potential outliers from 32 participants were detected and further investigated for quality control.
This example demonstrated how longitudinal models can provide CSRs to detect individual-specific outliers. CSRs should be considered as part of quality control for longitudinal epidemiologic studies.
Mammals harbor a dense commensal microbiota in the colon. Regulatory T (Treg) cells are known to limit microbe-triggered intestinal inflammation and the CD4
+ T cell compartment is shaped by the ...presence of particular microbes or bacterial compounds. It is, however, difficult to distinguish whether these effects reflect true mutualistic immune adaptation to intestinal colonization or rather idiosyncratic immune responses. To investigate truly mutualistic CD4
+ T cell adaptation, we used the altered Schaedler flora (ASF). Intestinal colonization resulted in activation and de novo generation of colonic Treg cells. Failure to activate Treg cells resulted in the induction of T helper 17 (Th17) and Th1 cell responses, which was reversed by wild-type Treg cells. Efficient Treg cell induction was also required to maintain intestinal homeostasis upon dextran sulfate sodium-mediated damage in the colon. Thus, microbiota colonization-induced Treg cell responses are a fundamental intrinsic mechanism to induce and maintain host-intestinal microbial T cell mutualism.
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► Intestinal Treg cells are induced and activated by benign commensal colonization ► Activation of intestinal Treg cells is required for successful CD4
+ T cell homeostasis ► Treg cell activation is intrinsic and not due to differences in the flora composition ► Maintenance of homeostasis also requires Treg cell activation
Chronic kidney disease (CKD) progression is typically characterized as either time to a clinically meaningful event (such as dialysis or transplant), or longitudinal changes in kidney function. This ...review describes pediatric kidney disease progression using these two distinct frameworks by reviewing and discussing data from the Chronic Kidney Disease in Children study. We first describe new equations to estimate glomerular filtration rate (GFR) for patients younger than age 25 years, and how the average of serum creatinine-based and cystatin C-based GFR equations yield valid estimates than either alone. Next, we present a life course description of CKD onset to kidney replacement therapy, prediction models based on clinical measurements, and show the importance of diagnosis (broadly classified as nonglomerular and glomerular in origin), GFR level, and proteinuria on progression. Literature on longitudinal GFR in children and young adults are reviewed and new data are presented to characterize nonlinear changes in estimated GFR in patients younger than age 25 years. These models showed accelerated progression associated with glomerular diagnosis, lower GFR level, and higher proteinuria, which was congruent with time-to-event analyses. Descriptions of online tools for GFR estimation and risk stratification for clinical applications are presented and we offer key epidemiologic considerations for the analysis of longitudinal pediatric CKD studies.
Background
Collagen X biomarker (CXM) is a novel biomarker of linear growth velocity. We investigated whether CXM correlated with measured growth velocity in children with impaired kidney function.
...Methods
We used data from children aged 2 through 16 years old enrolled in the Chronic Kidney Disease in Children (CKiD) study. We assessed the association between CXM level and growth velocity based on height measurements obtained at study visits using linear regression models constructed separately by sex, with and without adjustment for CKD covariates. Linear mixed-effects models were used to capture the between-individual and within-individual CXM changes over time associated with concomitant changes in growth velocity from baseline through follow-up.
Results
A total of 967 serum samples from 209 participants were assayed for CXM. CXM correlated more strongly in females compared to male participants. After adjustment for growth velocity and CKD covariates, only proteinuria in male participants affected CXM levels. Finally, we quantified the between- and within-participant associations between CXM level and growth velocity. A between-participant increase of 24% and 15% in CXM level in females and males, respectively, correlated with a 1 cm/year higher growth velocity. Within an individual participant, on average, 28% and 13% increases in CXM values in females and males, respectively, correlated with a 1 cm/year change in measured growth.
Conclusions
CXM measurement is potentially a valuable aid for monitoring growth in pediatric CKD. However, future research, including studies of CXM metabolism, is needed to clarify whether CXM can be a surrogate of growth in children with CKD.
Graphical Abstract
A higher resolution version of the Graphical abstract is available as
Supplementary information
Influenza A and B infections are a worldwide health concern to both humans and animals. High genetic evolution rates of the influenza virus allow the constant emergence of new strains and cause ...illness variation. Since human influenza infections are often complicated by secondary factors such as age and underlying medical conditions, strain or subtype specific clinical features are difficult to assess. Here we infected ferrets with 13 currently circulating influenza strains (including strains of pandemic 2009 H1N1 H1N1pdm and seasonal A/H1N1, A/H3N2, and B viruses). The clinical parameters were measured daily for 14 days in stable environmental conditions to compare clinical characteristics. We found that H1N1pdm strains had a more severe physiological impact than all season strains where pandemic A/California/07/2009 was the most clinically pathogenic pandemic strain. The most serious illness among seasonal A/H1N1 and A/H3N2 groups was caused by A/Solomon Islands/03/2006 and A/Perth/16/2009, respectively. Among the 13 studied strains, B/Hubei-Wujiagang/158/2009 presented the mildest clinical symptoms. We have also discovered that disease severity (by clinical illness and histopathology) correlated with influenza specific antibody response but not viral replication in the upper respiratory tract. H1N1pdm induced the highest and most rapid antibody response followed by seasonal A/H3N2, seasonal A/H1N1 and seasonal influenza B (with B/Hubei-Wujiagang/158/2009 inducing the weakest response). Our study is the first to compare the clinical features of multiple circulating influenza strains in ferrets. These findings will help to characterize the clinical pictures of specific influenza strains as well as give insights into the development and administration of appropriate influenza therapeutics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
As patients with chronic kidney disease (CKD) transition from pediatric nephrology care to adult care, their kidney function is clinically assessed by estimated glomerular filtration rate (eGFR) ...using both pediatric and adult equations, which may not be congruent. Here we evaluated commonly used eGFR equations and directly measured iohexol GFR (iGFR) among participants between ages 18 and 26 with a diagnosis of pediatric CKD in the Chronic Kidney Disease in Children (CKiD) cohort. The bedside serum creatinine (SCr)-only equation (CKiDSCr), the SCr-only CKD-EPI (CKD-EPISCr), the cystatin C (Cys)-only CKD-EPI (CKD-EPICys) and the combined SCr and Cys CKD-EPI (CKD-EPISCr-Cys) were compared with a) 279 measured iGFRs obtained from 187 participants and b) 548 eGFRs from the SCr and Cys-based CKiD equation (CKiDSCr-Cys) obtained from 219 participants. Among emerging adults with a median iGFR of 49 ml/min/1.73m2, the CKiDSCr-Cys equation had low bias (+1.5 ml/min/1.73m2) and high correlation (0.94), while CKiDSCr underestimated iGFR and CKiDSCr-Cys (–5.6 and –7.4 ml/min/1.73m2, respectively) and CKD-EPISCr had an overestimation bias (+8.2 and +6.1 ml/min/1.73m2, respectively). However, the CKD-EPICys and CKD-EPISCr-Cys exhibited strong agreement with both iGFR and CKiDSCr-Cys. GFR may also be validly estimated in this population by taking the simple average of CKiDSCr and CKD-EPISCr (average bias +1.3 compared to iGFR and -0.6 compared to CKiDSCr-Cys). Clinicians should be aware that individually the pediatric and adult SCr-based estimates of GFR had large discrepancies among emerging adults with pediatric CKD. Thus, when cystatin C is not available, we recommend the average of pediatric and adult SCr-based eGFR as a valid tool for clinical use.
The current clinical guidelines for vascular access do not have specific recommendations for older hemodialysis patients. Our study aimed to determine the association of age with arteriovenous ...fistula (AVF) placement, maturation, and primary and secondary patency loss among older hemodialysis recipients.
Retrospective cohort study.
A US national cohort of incident hemodialysis patients 67 years or older (N = 43,851) assembled from the US Renal Data System.
Age at dialysis initiation.
AVF placement, maturation, primary patency loss, and abandonment.
Cause-specific and subdistribution proportional hazards models were used to examine the association of age and AVF outcomes, with kidney transplantation, peritoneal dialysis, and death treated as competing events. Age cutoff was identified by restricted cubic splines. We compared crude and inverse probability–weighted cumulative incidence functions using Gray's test.
As compared with those aged 67-<77 years, patients 77 years or older had significantly lower probabilities of AVF placement (adjusted cause-specific HR cHR, 0.96 95% CI, 0.92-0.99; adjusted subdistribution HR sHR, 0.92 95% CI, 0.89-0.95; Gray's test P < 0.001) and maturation (adjusted cHR, 0.95 95% CI, 0.91-0.99; adjusted sHR, 0.93 95% CI, 0.90-0.97; P < 0.001). However, age was not associated with AVF primary (adjusted cHR, 1.05 95% CI, 1.00-1.11; adjusted sHR, 1.04 95% CI, 0.99-1.09; P = 0.09) or secondary (adjusted cHR, 1.06 95% CI, 0.94-1.20; adjusted sHR, 1.05 95% CI, 0.93-1.18; P = 0.4) patency loss.
Reliance on administrative claims to ascertain AVF outcomes.
The likelihood of AVF maturation is an important consideration for vascular access planning. Age alone should not be the basis for excluding older dialysis patients from AVF creation because maintenance of fistula patency was not reduced with older age despite a modest reduction in fistula maturation
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Studies of adults have demonstrated an association between metabolic acidosis, as measured by low serum bicarbonate levels, and CKD progression. We evaluated this relationship in children using data ...from the Chronic Kidney Disease in Children study.
The relationship between serum bicarbonate and a composite end point, defined as 50% decline in eGFR or KRT, was described using parametric and semiparametric survival methods. Analyses were stratified by underlying nonglomerular and glomerular diagnoses, and adjusted for demographic characteristics, eGFR, proteinuria, anemia, phosphate, hypertension, and alkali therapy.
Six hundred and three participants with nonglomerular disease contributed 2673 person-years of follow-up, and 255 with a glomerular diagnosis contributed 808 person-years of follow-up. At baseline, 39% (237 of 603) of participants with nonglomerular disease had a bicarbonate level of ≤22 meq/L and 36% (85 of 237) of those participants reported alkali therapy treatment. In participants with glomerular disease, 31% (79 of 255) had a bicarbonate of ≤22 meq/L, 18% (14 of 79) of those participants reported alkali therapy treatment. In adjusted longitudinal analyses, compared with participants with a bicarbonate level >22 meq/L, hazard ratios associated with a bicarbonate level of <18 meq/L and 19-22 meq/L were 1.28 95% confidence interval (95% CI), 0.84 to 1.94 and 0.91 (95% CI, 0.65 to 1.26), respectively, in children with nonglomerular disease. In children with glomerular disease, adjusted hazard ratios associated with bicarbonate level ≤18 meq/L and bicarbonate 19-22 meq/L were 2.16 (95% CI, 1.05 to 4.44) and 1.74 (95% CI, 1.07 to 2.85), respectively. Resolution of low bicarbonate was associated with a lower risk of CKD progression compared with persistently low bicarbonate (≤22 meq/L).
In children with glomerular disease, low bicarbonate was linked to a higher risk of CKD progression. Resolution of low bicarbonate was associated with a lower risk of CKD progression. Fewer than one half of all children with low bicarbonate reported treatment with alkali therapy. Long-term studies of alkali therapy's effect in patients with pediatric CKD are needed.
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