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
Recenzirano
Odprti dostop
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.
Identification of novel risk factors for chronic kidney disease (CKD) progression may inform mechanistic investigations and improve identification of high-risk subgroups. The current study aimed to ...characterize CKD progression across levels of numerous risk factors and identify independent risk factors for CKD progression among those with and without diabetes.
The Chronic Renal Insufficiency Cohort (CRIC) Study is a prospective cohort study of adults with CKD conducted at 7 US clinical centers.
Participants (N=3,379) had up to 12.3 years of follow-up; 47% had diabetes.
30 risk factors for CKD progression across sociodemographic, behavioral, clinical, and biochemical domains at baseline.
Study outcomes were estimated glomerular filtration rate (eGFR) slope and the composite of halving of eGFR or initiation of kidney replacement therapy.
Stepwise selection of independent risk factors was performed stratified by diabetes status using linear mixed-effects and Cox proportional hazards models.
Among those without and with diabetes, respectively, mean eGFR slope was−1.4±3.3 and−2.7±4.7mL/min/1.73m2 per year. Among participants with diabetes, multivariable-adjusted hazard of the composite outcome was approximately 2-fold or greater with higher levels of the inflammatory chemokine CXCL12, the cardiac marker N-terminal pro–B-type natriuretic peptide (NT-proBNP), and the kidney injury marker urinary neutrophil gelatinase-associated lipocalin (NGAL). Among those without diabetes, low serum bicarbonate and higher high-sensitivity troponin T, NT-proBNP, and urinary NGAL levels were all significantly associated with a 1.5-fold or greater rate of the composite outcome.
The observational study design precludes causal inference.
Strong associations for cardiac markers, plasma CXCL12, and urinary NGAL are comparable to that of systolic blood pressure≥140mm Hg, a well-established risk factor for CKD progression. This warrants further investigation into the potential mechanisms that these markers indicate and opportunities to use them to improve risk stratification.
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Sex-Related Disparities in CKD Progression Ricardo, Ana C; Yang, Wei; Sha, Daohang ...
Journal of the American Society of Nephrology,
01/2019, Letnik:
30, Številka:
1
Journal Article
Recenzirano
Odprti dostop
In the United States, incidence of ESRD is 1.5 times higher in men than in women, despite men's lower prevalence of CKD. Prior studies, limited by inclusion of small percentages of minorities and ...other factors, suggested that men have more rapid CKD progression, but this finding has been inconsistent.
In our prospective investigation of sex differences in CKD progression, we used data from 3939 adults (1778 women and 2161 men) enrolled in the Chronic Renal Insufficiency Cohort Study, a large, diverse CKD cohort. We evaluated associations between sex (women versus men) and outcomes, specifically incident ESRD (defined as undergoing dialysis or a kidney transplant), 50% eGFR decline from baseline, incident CKD stage 5 (eGFR<15 ml/min per 1.73 m
), eGFR slope, and all-cause death.
Participants' mean age was 58 years at study entry; 42% were non-Hispanic black, and 13% were Hispanic. During median follow-up of 6.9 years, 844 individuals developed ESRD, and 853 died. In multivariable regression models, compared with men, women had significantly lower risk of ESRD, 50% eGFR decline, progression to CKD stage 5, and death. The mean unadjusted eGFR slope was -1.09 ml/min per 1.73 m
per year in women and -1.43 ml/min per 1.73 m
per year in men, but this difference was not significant after multivariable adjustment.
In this CKD cohort, women had lower risk of CKD progression and death compared with men. Additional investigation is needed to identify biologic and psychosocial factors underlying these sex-related differences.
Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 is thought to be an early biomarker of disordered phosphorus ...metabolism in the initial stages of chronic kidney disease (CKD). We measured FGF23 in baseline samples from 3879 patients in the Chronic Renal Insufficiency Cohort study, which is a diverse cohort of patients with CKD stage 2–4. Mean serum phosphate and median parathyroid hormone (PTH) levels were in the normal range, but median FGF23 was markedly greater than in healthy populations, and increased significantly with decreasing estimated glomerular filtration rate (eGFR). High levels of FGF23, defined as being above 100RU/ml, were more common than secondary hyperparathyroidism and hyperphosphatemia in all strata of eGFR. The threshold of eGFR at which the slope of FGF23 increased was significantly higher than the corresponding threshold for PTH based on non-overlapping 95% confidence intervals. Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increased phosphate or PTH. Hence, FGF23 measurements may be a sensitive early biomarker of disordered phosphorus metabolism in patients with CKD and normal serum phosphate levels.
Current dietary guidelines recommend that patients with chronic kidney disease (CKD) restrict individual nutrients, such as sodium, potassium, phosphorus, and protein. This approach can be difficult ...for patients to implement and ignores important nutrient interactions. Dietary patterns are an alternative method to intervene on diet. Our objective was to define the associations of 4 healthy dietary patterns with risk for CKD progression and all-cause mortality among people with CKD.
Prospective cohort study.
2,403 participants aged 21 to 74 years with estimated glomerular filtration rates of 20 to 70mL/min/1.73m2 and dietary data in the Chronic Renal Insufficiency Cohort (CRIC) Study.
Healthy Eating Index-2015, Alternative Healthy Eating Index-2010, alternate Mediterranean diet (aMed), and Dietary Approaches to Stop Hypertension (DASH) diet scores were calculated from food frequency questionnaires.
(1) CKD progression defined as≥50% estimated glomerular filtration rate decline, kidney transplantation, or dialysis and (2) all-cause mortality.
Cox proportional hazards regression models adjusted for demographic, lifestyle, and clinical covariates to estimate hazard ratios (HRs) and 95% CIs.
There were 855 cases of CKD progression and 773 deaths during a maximum of 14 years. Compared with participants with the lowest adherence, the most highly adherent tertile of Alternative Healthy Eating Index-2010, aMed, and DASH had lower adjusted risk for CKD progression, with the strongest results for aMed (HR, 0.75; 95% CI, 0.62-0.90). Compared with participants with the lowest adherence, the highest adherence tertiles for all scores had lower adjusted risk for all-cause mortality for each index (24%-31% lower risk).
Self-reported dietary intake.
Greater adherence to several healthy dietary patterns is associated with lower risk for CKD progression and all-cause mortality among people with CKD. Guidance to adopt healthy dietary patterns can be considered as a strategy for managing CKD.
The inclusion of race in equations to estimate the glomerular filtration rate (GFR) has become controversial. Alternative equations that can be used to achieve similar accuracy without the use of ...race are needed.
In a large national study involving adults with chronic kidney disease, we conducted cross-sectional analyses of baseline data from 1248 participants for whom data, including the following, had been collected: race as reported by the participant, genetic ancestry markers, and the serum creatinine, serum cystatin C, and 24-hour urinary creatinine levels.
Using current formulations of GFR estimating equations, we found that in participants who identified as Black, a model that omitted race resulted in more underestimation of the GFR (median difference between measured and estimated GFR, 3.99 ml per minute per 1.73 m
of body-surface area; 95% confidence interval CI, 2.17 to 5.62) and lower accuracy (percent of estimated GFR within 10% of measured GFR P
, 31%; 95% CI, 24 to 39) than models that included race (median difference, 1.11 ml per minute per 1.73 m
; 95% CI, -0.29 to 2.54; P
, 42%; 95% CI, 34 to 50). The incorporation of genetic ancestry data instead of race resulted in similar estimates of the GFR (median difference, 1.33 ml per minute per 1.73 m
; 95% CI, -0.12 to 2.33; P
, 42%; 95% CI, 34 to 50). The inclusion of non-GFR determinants of the serum creatinine level (e.g., body-composition metrics and urinary excretion of creatinine) that differed according to race reported by the participants and genetic ancestry did not eliminate the misclassification introduced by removing race (or ancestry) from serum creatinine-based GFR estimating equations. In contrast, the incorporation of race or ancestry was not necessary to achieve similarly statistically unbiased (median difference, 0.33 ml per minute per 1.73 m
; 95% CI, -1.43 to 1.92) and accurate (P
, 41%; 95% CI, 34 to 49) estimates in Black participants when GFR was estimated with the use of cystatin C.
The use of the serum creatinine level to estimate the GFR without race (or genetic ancestry) introduced systematic misclassification that could not be eliminated even when numerous non-GFR determinants of the serum creatinine level were accounted for. The estimation of GFR with the use of cystatin C generated similar results while eliminating the negative consequences of the current race-based approaches. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).
Abstract
Background
Protein carbamylation is a post-translational protein modification caused, in part, by exposure to urea’s dissociation product cyanate. Carbamylation is linked to cardiovascular ...outcomes and mortality in dialysis-dependent end-stage kidney disease (ESKD), but its effects in earlier pre-dialysis stages of chronic kidney disease (CKD) are not established.
Methods
We conducted two nested case–control studies within the Chronic Renal Insufficiency Cohort Study. First, we matched 75 cases demonstrating CKD progression 50% estimated glomerular filtration rate (eGFR) reduction or reaching ESKD to 75 controls (matched on baseline eGFR, 24-h proteinuria, age, sex and race). In the second study, we similarly matched 75 subjects who died during follow-up (cases) to 75 surviving controls. Baseline carbamylated albumin levels (C-Alb, a validated carbamylation assay) were compared between cases and controls in each study.
Results
At baseline, in the CKD progression study, other than blood urea nitrogen (BUN) and smoking status, there were no significant differences in any matched or other parameter. In the mortality group, the only baseline difference was smoking status. Adjusting for baseline differences, the top tertile of C-Alb was associated with an increased risk of CKD progression odds ratio (OR) = 7.9; 95% confidence interval (CI) 1.9–32.8; P = 0.004 and mortality (OR = 3.4; 95% CI 1.0–11.4; P = 0.05) when compared with the bottom tertile. C-Alb correlated with eGFR but was more strongly correlated with BUN.
Conclusions
Our data suggest that protein carbamylation is a predictor of CKD progression, beyond traditional risks including eGFR and proteinuria. Carbamylation’s association with mortality was smaller in this limited sample size.
Graphical Abstract
Graphical Abstract
Data on rates of heart failure (HF) hospitalizations, recurrent hospitalizations, and outcomes related to HF hospitalizations in chronic kidney disease (CKD) are limited.
This study examined rates of ...HF hospitalizations and re-hospitalizations within a large CKD population and evaluated the burden of HF hospitalizations with the risk of subsequent CKD progression and death.
The prospective CRIC (Chronic Renal Insufficiency Cohort) study measured the estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR) at baseline. The crude rates and rate ratios of HF hospitalizations and 30-day HF re-hospitalizations were calculated using Poisson regression models. Cox regression was used to assess the association of the frequency of HF hospitalizations within the first 2 years of follow-up with risk of subsequent CKD progression and death.
Among 3,791 participants, the crude rate of HF admissions was 5.8 per 100 person-years (with higher rates of HF with preserved ejection fraction vs. HF with reduced ejection fraction). The adjusted rate of HF was higher with a lower eGFR (vs. eGFR >45 ml/min/1.73 m2); the rate ratios were 1.7 and 2.2 for eGFR 30 to 44 and <30 ml/min/1.73 m2 (vs. >45 ml/min/1.73 m2), respectively. Similarly, the adjusted rates of HF hospitalization were significantly higher in those with higher urine ACR (vs. urine ACR <30 mg/g); the rate ratios were 1.9 and 2.6 for urine ACR 30 to 299 and ≥300 mg/g, respectively. Overall, 20.6% of participants had a subsequent HF re-admission within 30 days. HF hospitalization within 2 years of study entry was associated with greater adjusted risks for CKD progression (1 hospitalization: hazard ratio HR: 1.93; 95% confidence interval CI: 1.40 to 2.67; 2+ hospitalizations: HR: 2.14; 95% CI: 1.30 to 3.54) and all-cause death (1 hospitalization: HR: 2.20; 95% CI: 1.71 to 2.84; 2+ hospitalizations: HR: 3.06; 95% CI: 2.23 to 4.18).
Within a large U.S. CKD population, the rates of HF hospitalizations and re-hospitalization were high, with even higher rates across categories of lower eGFR and higher urine ACR. Patients with CKD hospitalized with HF had greater risks of CKD progression and death. HF prevention and treatment should be a public health priority to improve CKD outcomes.
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Groundwater ecosystems remain poorly understood yet may provide ecosystem services, make a unique contribution to biodiversity and contain useful bio-indicators of water quality. Little is known ...about ecosystem variability, the distribution of invertebrates within aquifers, or how representative boreholes are of aquifers. We addressed these issues using borehole imaging and single borehole dilution tests to identify three potential aquifer habitats (fractures, fissures or conduits) intercepted by two Chalk boreholes at different depths beneath the surface (34 to 98 m). These habitats were characterised by sampling the invertebrates, microbiology and hydrochemistry using a packer system to isolate them. Samples were taken with progressively increasing pumped volume to assess differences between borehole and aquifer communities. The study provides a new conceptual framework to infer the origin of water, invertebrates and microbes sampled from boreholes. It demonstrates that pumping 5 m(3) at 0.4-1.8 l/sec was sufficient to entrain invertebrates from five to tens of metres into the aquifer during these packer tests. Invertebrates and bacteria were more abundant in the boreholes than in the aquifer, with associated water chemistry variations indicating that boreholes act as sites of enhanced biogeochemical cycling. There was some variability in invertebrate abundance and bacterial community structure between habitats, indicating ecological heterogeneity within the aquifer. However, invertebrates were captured in all aquifer samples, and bacterial abundance, major ion chemistry and dissolved oxygen remained similar. Therefore the study demonstrates that in the Chalk, ecosystems comprising bacteria and invertebrates extend from around the water table to 70 m below it. Hydrogeological techniques provide excellent scope for tackling outstanding questions in groundwater ecology, provided an appropriate conceptual hydrogeological understanding is applied.
Complex nonlinear models are typically ill conditioned or sloppy; their predictions are significantly affected by only a small subset of parameter combinations, and parameters are difficult to ...reconstruct from model behavior. Despite forming an important universality class and arising frequently in practice when performing a nonlinear fit to data, formal and systematic explanations of sloppiness are lacking. By unifying geometric interpretations of sloppiness with Chebyshev approximation theory, we rigorously explain sloppiness as a consequence of model smoothness. Our approach results in universal bounds on model predictions for classes of smooth models, capturing global geometric features that are intrinsic to their model manifolds, and characterizing a universality class of models. We illustrate this universality using three models from disparate fields (physics, chemistry, biology): exponential curves, reaction rates from an enzyme-catalyzed chemical reaction, and an epidemiology model of an infected population.
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