Inflammation and Progression of CKD: The CRIC Study Amdur, Richard L; Feldman, Harold I; Gupta, Jayanta ...
Clinical journal of the American Society of Nephrology,
09/2016, Letnik:
11, Številka:
9
Journal Article
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CKD is a global public health problem with significant mortality and morbidity.
We examined the multivariable association of plasma levels of IL-1, IL-1 receptor antagonist, IL-6, TNF-α, TGF-β, ...high-sensitivity C-reactive protein, fibrinogen, and serum albumin with progression of CKD in 3430 Chronic Renal Insufficiency Cohort study participants.
Over a median follow-up time of 6.3 years, 899 participants reached the composite end point of ≥50% decline in eGFR from baseline or onset of ESRD. Elevated plasma levels of fibrinogen, IL-6, and TNF-α and lower serum albumin were associated with a greater decline in eGFR over time. After adjusting for demographics, BP, laboratory variables, medication use, and baseline eGFR, hazard ratios for the composite outcome were greater for the patients in the highest quartile of fibrinogen (hazard ratio, 2.05; 95% confidence interval, 1.64 to 2.55; P<0.001), IL-6 (hazard ratio, 1.44; 95% confidence interval, 1.17 to 1.77; P<0.01), and TNF-α (hazard ratio, 1.94; 95% confidence interval, 1.52 to 2.47; P<0.001) compared with those in the respective lowest quartiles. The hazard ratio was 3.48 (95% confidence interval, 2.88 to 4.21; P<0.001) for patients in the lowest serum albumin quartile relative to those in the highest quartile. When also adjusted for albuminuria, the associations of fibrinogen (hazard ratio, 1.49; 95% confidence interval, 1.20 to 1.86; P<0.001), serum albumin (hazard ratio, 1.52; 95% confidence interval, 1.24 to 1.87; P<0.001), and TNF-α (hazard ratio, 1.42; 95% confidence interval, 1.11 to 1.81; P<0.001) with outcome were attenuated but remained significant.
Elevated plasma levels of fibrinogen and TNF-α and decreased serum albumin are associated with rapid loss of kidney function in patients with CKD.
Background Atopic dermatitis (AD) is a common skin disease that is characterized by recurrent episodes of itching. Filaggrin ( FLG ) loss-of-function ( FLG null) mutations have been associated with ...an increased risk of AD. Objective We sought to evaluate the effect of individual FLG null mutations on the persistence of AD over time. Methods We evaluated a multiyear prospective cohort study of children with AD with respect to FLG null mutations (R501X, 2282del4, R2447X, and S3247X). We evaluated the association of these mutations with the persistence of AD symptoms over time with respect to reports of no symptoms of AD and whether topical medication was needed for symptom resolution. Results Eight hundred fifty-seven subjects were followed for 3684 person-years. One or more FLG null mutations were noted in 16.3% of subjects and specifically in 27.5% of white subjects and 5.8% of African American subjects. Subjects with an FLG null mutation were less likely (odds ratio OR, 0.54; 95% CI, 0.41-0.71) to report that their skin was symptom free at any time compared with those without an FLG null mutation. The effect of these mutations was similar in white subjects (OR, 0.42; 95% CI, 0.31-0.57) and African-American subjects (OR, 0.53; 95% CI, 0.25-1.12; P = .62). Children with the R501X mutation (OR, 0.44; 95% CI, 0.22-0.88) were the least responsive to therapy. Conclusions In a US cohort with AD, FLG null mutations were common. Children with FLG null mutations were more likely to have persistent AD. Although these mutations were more common in those of European ancestry, their effect on persistence was similar in those of African ancestry. Response to therapy was not uniform among children with FLG null mutations.
Atopic dermatitis (AD), food allergy, allergic rhinitis, and asthma are common atopic disorders of complex etiology. The frequently observed atopic march from early AD to asthma, allergic rhinitis, ...or both later in life and the extensive comorbidity of atopic disorders suggest common causal mechanisms in addition to distinct ones. Indeed, both disease-specific and shared genomic regions exist for atopic disorders. Their prevalence also varies among races; for example, AD and asthma have a higher prevalence in African Americans when compared with European Americans. Whether this disparity stems from true genetic or race-specific environmental risk factors or both is unknown. Thus far, the majority of the genetic studies on atopic diseases have used populations of European ancestry, limiting their generalizability. Large-cohort initiatives and new analytic methods, such as admixture mapping, are currently being used to address this knowledge gap. Here we discuss the unique and shared genetic risk factors for atopic disorders in the context of ancestry variations and the promise of high-throughput “-omics”–based systems biology approach in providing greater insight to deconstruct their genetic and nongenetic etiologies. Future research will also focus on deep phenotyping and genotyping of diverse racial ancestry, gene-environment, and gene-gene interactions.
Increased risk of mortality in patients with CKD has been attributed to inflammation. However, the association between kidney function, albuminuria, and biomarkers of inflammation has not been ...examined in a large cohort of CKD patients.
This study measured the plasma levels of IL-1β, IL-1 receptor antagonist (IL-1RA), IL-6, TNF-α, TGF-β, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and serum albumin in 3939 participants enrolled in the Chronic Renal Insufficiency Cohort study between June 2003 and September 2008. An inflammation score was established based on plasma levels of IL-1β, IL-6, TNF-α, hs-CRP, and fibrinogen. Estimated GFR (eGFR) and serum cystatin C were used as measures of kidney function. Albuminuria was quantitated by urine albumin to creatinine ratio (UACR).
Plasma levels of IL-1β, IL-1RA, IL-6, TNF-α, hs-CRP, and fibrinogen were higher among participants with lower levels of eGFR. Inflammation score was higher among those with lower eGFR and higher UACR. In regression analysis adjusted for multiple covariates, eGFR, cystatin C, and UACR were strongly associated with fibrinogen, serum albumin, IL-6, and TNF-α. Each unit increase in eGFR, cystatin C, and UACR was associated with a -1.2% (95% confidence interval, -1.4, -1), 64.9% (56.8, 73.3) and 0.6% (0.4, 0.8) change in IL-6, respectively (P<0.001).
Biomarkers of inflammation were inversely associated with measures of kidney function and positively with albuminuria.
Background Atopic dermatitis (AD) is a common skin disease characterized by recurrent episodes of itching. Genetic variation associated with the persistence of AD has not been described for African ...American subjects. Objective We sought to evaluate genetic variation of filaggrin-2 (FLG2) in African American subjects with AD. Methods We evaluated a multiyear prospective cohort study of African American children with AD with respect to FLG2 variation based on whole-exome sequencing, followed by a targeted analysis. We ultimately evaluated the association of rs12568784 and rs16833974 with respect to the persistence of AD symptoms over time. Results Whole-exome analysis was conducted on 60 subjects, revealing a premature stop codon in exon 3 at S2377X (rs12568784) and X2392S (rs150529054) and a large exon 3 deletion mutation, Q2053del224. On the basis of a priori criteria, we then studied rs12568784, rs16833974 (H1249R), and Q2053del224. We noted that patients with S2377X (odds ratio OR, 0.44; 95% CI, 0.25-0.46) and H1249R (OR, 0.23; 05% CI, 0.12-0.46) were significantly less likely to be free of symptoms of AD, and Q2053del224 (OR, 0.54; 95% CI, 0.16-1.80) trended toward this outcome. S2377X and H1249R were in high linkage disequilibrium (D′ = 0.95). Conclusions In an African American cohort with AD, FLG2 mutations were associated with more persistent AD. This is the first finding of genetic variation of a skin barrier protein in subjects of African ancestry with AD.
Atopic dermatitis (AD) is a common chronic illness of childhood.
To evaluate the association between thymic stromal lymphopoietin (TSLP) variation and the persistence of skin symptoms of AD.
A ...prospective cohort study was conducted in the general community. Participants included 796 children enrolled in the Pediatric Eczema Elective Registry. EXPOSURE Evaluation of TSLP variation.
Self-reported outcome of whether a child's skin had no symptoms of AD and required no medications for 6 months at 6-month intervals.
We evaluated 14 variants of TSLP. The variant rs1898671 was significantly associated with the outcome in white children (P = .01). As measured by overlapping CIs, similar odds ratios (ORs) were noted among whites (OR, 1.72; 95% CI, 1.11-2.66) and African Americans (1.33; 0.52-3.45). Further within the subcohort of individuals with a filaggrin protein (FLG) loss-of-function mutation, those with TSLP variation were more likely to have less-persistent disease (OR, 4.92; 95% CI, 2.04-11.86).
The TSLP variation is associated with less persistent AD. Therefore, TSLP may be a potential therapeutic target for the treatment of AD, especially in individuals with diminished barrier function due to FLG mutations. This is an attractive hypothesis that can be tested in clinical trials.
Chronic kidney disease (CKD) and arterial stiffness are associated with increased cardiovascular morbidity and mortality. Inflammation is proposed to have a role in the development of arterial ...stiffness, and CKD is recognized as a proinflammatory state. Arterial stiffness is increased in CKD, and cross-sectional data has suggested a link between increased inflammatory markers in CKD and higher measures of arterial stiffness. However, no large scale investigations have examined the impact of inflammation on the progression of arterial stiffness in CKD.
We performed baseline assessments of 5 inflammatory markers in 3,939 participants from the chronic renal insufficiency cohort (CRIC), along with serial measurements of arterial stiffness at 0, 2, and 4 years of follow-up.
A total of 2,933 participants completed each of the follow-up stiffness measures. In cross-sectional analysis at enrollment, significant associations with at least 2 measures of stiffness were observed for fibrinogen, interleukin-6, high-sensitivity C-reactive protein, proteinuria, and composite inflammation score after adjustment for confounders. In longitudinal analyses, there were few meaningful correlations between baseline levels of inflammation and changes in metrics of arterial stiffness over time.
In a large cohort of CKD participants, we observed multiple significant correlations between initial markers of inflammation and metrics of arterial stiffness, but baseline inflammation did not predict changes in arterial stiffness over time. While well-described biologic mechanisms provide the basis for our understanding of the cross-sectional results, continued efforts to design longitudinal studies are necessary to fully elucidate the relationship between chronic inflammation and arterial stiffening.
Autophagy is a cellular process directed at eliminating or recycling cellular proteins. Recently, the autophagy pathway has been implicated in immune dysfunction, the pathogenesis of inflammatory ...disorders, and response to viral infection. Associations between two genes in the autophagy pathway, ATG5 and ATG7, with childhood asthma were investigated.
Using genetic and experimental approaches, we examined the association of 13 HapMap-derived tagging SNPs in ATG5 and ATG7 with childhood asthma in 312 asthmatic and 246 non-allergic control children. We confirmed our findings by using independent cohorts and imputation analysis. Finally, we evaluated the functional relevance of a disease associated SNP.
We demonstrated that ATG5 single nucleotide polymorphisms rs12201458 and rs510432 were associated with asthma (p = 0.00085 and 0.0025, respectively). In three independent cohorts, additional variants in ATG5 in the same LD block were associated with asthma (p<0.05). We found that rs510432 was functionally relevant and conferred significantly increased promotor activity. Furthermore, Atg5 expression was increased in nasal epithelium of acute asthmatics compared to stable asthmatics and non-asthmatic controls.
Genetic variants in ATG5, including a functional promotor variant, are associated with childhood asthma. These results provide novel evidence for a role for ATG5 in childhood asthma.
Purpose. To determine and compare OHRQoL (oral-health-related quality of life) using the Geriatric Oral Health Assessment Index (GOHAI-12) and Oral Health Impact Profile (OHIP-14) among patients ...receiving hemodialysis (HD). Methods. Face-to-face interviews and intraoral examinations were conducted among 70 patients. Mann–Whitney U test and Kruskal–Wallis test were used to compare each item score with demographics and dental and overall health status. Results. The mean number of years on dialysis was 4.7 ± 7.5 yrs; the mean number of teeth present was 19.7 ± 11.04; median values of OHRQoL using GOHAI-12 and OHIP-14 were 52 and 64. Within GOHAI-12, limiting food (p 0.043), uncomfortable eating in front of people (p 0.045), limiting contact with people (p 0.046), and eating without discomfort (p 0.011) were significantly associated with females. Being worried (p 0.040) and self-conscious (p 0.048) were significant for age groups ≤65 years. Prevented from speaking was associated with >20 teeth (p 0.016). Being worried about oral health was associated with number of years on dialysis (p 0.042). Within OHIP-14, speech was associated with number of teeth present (p 0.024). Total inability to function was significantly associated with race (p 0.018), number of teeth (p 0.028), and edentulousness (p 0.031). Conclusions. GOHAI-12 was more effective than OHIP-14 in assessing OHRQoL. However, most subjective experiences did not correlate with clinical findings. Systemic health issue like end-stage renal disease affecting QoL might have taken precedence over dental problems. Clinical assessments should be inherent in oral-health evaluation and there should be cooperation between nephrologists and dentists in promoting oral health and treating systemic conditions among HD patients.
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