Discovery and Biosynthesis of the Amodesmycins, Aromatic Polyketide-Siderophore Hybrid Conjugates.

A type II polyketide synthase biosynthetic gene cluster (amd) containing three P450 genes was identified from a soil metagenomic library, and novel benz[h]isoquinoline-desferrioxamine B conjugated compound amodesmycins were isolated from Streptomyces albus J1074 harboring the amd gene cluster. Genetic evidence showed that the benz[h]isoquinoline part and desferrioxamine B part in amodesmycins were derived from the amd gene cluster and S. albus J1074, respectively, while P450 enzymes played critical roles in the conjunction of these two parts.

Salumycin, a New Pyrazolequinone from a Streptomyces albus J1074 Mutant Strain.

Heterocyclic natural products with various bioactivities play significant roles in pharmaceuticals. Here, we isolated a heterocyclic compound salumycin (1) from a Streptomyces albus J1074 mutant strain. The structure of (1) was elucidated via single-crystal X-ray diffraction, mass spectrometry (MS), fourier transform infrared spectrometer (FTIR), and nuclear magnetic resonance (NMR) data analysis. Salumycin (1) contained a novel pyrazolequinone ring, which had never been previously reported in a natural product. Salumycin (1) exhibited moderate 2,2'-diphenyl-1-picrylhydrazyl (DPPH)-radical scavenging activity (EC50 = 46.3 ± 2.2 µM) compared with tert-butylhydroquinone (EC50 = 4.7 ± 0.3 µM). This study provides a new example of discovering novel natural products from bacteria.

Serum Bicarbonate and Structural and Functional Cardiac Abnormalities in Chronic Kidney Disease - A Report from the Chronic Renal Insufficiency Cohort Study.

BACKGROUND: Heart failure (HF) is a frequent occurrence in chronic kidney disease (CKD) patients and predicts poor survival. Serum bicarbonate is associated with increased rates of HF in CKD; however, the mechanisms leading to this association are incompletely understood. This study aims to assess whether serum bicarbonate is independently associated with structural and functional cardiac abnormalities in CKD. METHODS: The association between serum bicarbonate and left ventricular (LV) hypertrophy (LVH), LV mass indexed to height2.7, LV geometry, ejection fraction (EF) and diastolic dysfunction was assessed in 3,483 participants without NYHA class III/IV HF, enrolled in the Chronic Renal Insufficiency Cohort study. RESULTS: The mean estimated glomerular filtration rate was 42.5 ± 17 ml/min/1.73 m2. The overall prevalence of LVH was 51.2%, with 57.8, 50.9 and 47.7% for bicarbonate categories <22, 22-26 and >26 mmol/l, respectively. Participants with low bicarbonate were more likely to have LVH and abnormal LV geometry (OR 1.32; 95% CI 1.07-1.64, and OR 1.57; 95% CI 1.14-2.16, respectively). However, the association was not statistically significant after adjustment for demographics, traditional cardiovascular risk factors, medications and kidney function (OR 1.07; 95% CI 0.66-1.72, and OR 1.27; 95% CI 0.64-2.51, respectively). No association was found between bicarbonate and systolic or diastolic dysfunction. During follow-up, no significant changes in LV mass or EF were observed in any bicarbonate strata. CONCLUSIONS: In a large CKD study, serum bicarbonate was associated with LV mass and concentric LVH; however, this association was attenuated after adjustment for clinical factors suggesting that the observed cardiac effects are mediated through yet unknown mechanisms.

Race/Ethnicity and Cardiovascular Outcomes in Adults With CKD: Findings From the CRIC (Chronic Renal Insufficiency Cohort) and Hispanic CRIC Studies.

BACKGROUND: Non-Hispanic blacks and Hispanics with end-stage renal disease have a lower risk for death than non-Hispanic whites, but data for racial/ethnic variation in cardiovascular outcomes for non-dialysis-dependent chronic kidney disease are limited. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: 3,785 adults with entry estimated glomerular filtration rates of 20 to 70mL/min/1.73m(2) enrolled in the CRIC (Chronic Renal Insufficiency Cohort) Study. PREDICTORS: Race/ethnicity (non-Hispanic white, non-Hispanic black, and Hispanic). OUTCOMES: Cardiovascular outcomes (atherosclerotic events [myocardial infarction, stroke, or peripheral arterial disease] and heart failure) and a composite of each cardiovascular outcome or all-cause death. MEASUREMENTS: Multivariable Cox proportional hazards. RESULTS: During a median follow-up of 6.6 years, we observed 506 atherosclerotic events, 551 heart failure events, and 692 deaths. In regression analyses, there were no significant differences in atherosclerotic events among the 3 racial/ethnic groups. In analyses stratified by clinical site, non-Hispanic blacks had a higher risk for heart failure events (HR, 1.59; 95% CI, 1.29-1.95), which became nonsignificant after adjustment for demographic factors and baseline kidney function. In contrast, Hispanics had similar risk for heart failure events as non-Hispanic whites. In analyses stratified by clinical site, compared with non-Hispanic whites, non-Hispanic blacks were at similar risk for atherosclerotic events or death. However, after further adjustment for cardiovascular risk factors, medications, and mineral metabolism markers, non-Hispanic blacks had 17% lower risk for the outcome (HR, 0.83; 95% CI, 0.69-0.99) than non-Hispanic whites, whereas there was no significant association with Hispanic ethnicity. LIMITATIONS: Hispanics were largely recruited from a single center, and the study was underpowered to evaluate the association between Hispanic ethnicity and mortality. CONCLUSIONS: There were no significant racial/ethnic differences in adjusted risk for atherosclerotic or heart failure outcomes. Future research is needed to better explain the reduced risk for atherosclerotic events or death in non-Hispanic blacks compared with non-Hispanic whites.

Influence of Nephrologist Care on Management and Outcomes in Adults with Chronic Kidney Disease.

BACKGROUND: Predialysis nephrology care for adults with late stage chronic kidney disease (CKD) is associated with improved outcomes. Less is known about the effects of nephrology care in earlier stages of CKD. OBJECTIVE: We aimed to evaluate the effect of nephrology care on management of CKD risk factors and complications, CKD progression, incident cardiovascular disease (CVD), and death. DESIGN: This was a prospective cohort study. PARTICIPANTS: Participants included 3855 men and women aged 21 to 74 years enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study with a mean (SD) estimated glomerular filtration rate (eGFR) at entry of 45 (17) ml/min/1.73 m(2), followed for a median of 6.6 years. MAIN MEASURES: The main predictor was self-reported prior contact with a nephrologist at study enrollment. Outcomes evaluated included CKD progression (≥ 50 % eGFR loss or end-stage renal disease), incident CVD, and death. RESULTS: Two-thirds (67 %) of the participants reported prior contact with a nephrologist at study enrollment. They were younger, more likely to be male, non-Hispanic white, and had lower eGFR and higher urine protein (p < 0.05). A subgroup with eGFR 30- < 60 ml/min/1.73 m(2) and prior contact with a nephrologist were more likely to receive pharmacologic treatment for CKD-related complications and to report angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (ACEi/ARB) use. After propensity score matching (for reporting prior contact with a nephrologist vs. not) and adjusting for demographic and clinical variables, prior contact with a nephrologist was not significantly associated with CKD progression, incident CVD or death (p > 0.05). CONCLUSIONS: One-third of CRIC participants had not seen a nephrologist before enrollment, and this prior contact was subject to age, sex, and ethnic-related disparities. While prior nephrology care was associated with more frequent treatment of CKD complications and use of ACEi/ARB medications, there was neither an association between this care and achievement of guideline-recommended intermediate measures, nor long-term adverse outcomes.

The role of renin-angiotensin-aldosterone system genes in the progression of chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) study.

BACKGROUND: We conducted single-marker, gene- and pathway-based analyses to examine the association between renin-angiotensin-aldosterone system (RAAS) variants and chronic kidney disease (CKD) progression among Chronic Renal Insufficiency Cohort study participants. METHODS: A total of 1523 white and 1490 black subjects were genotyped for 490 single nucleotide polymorphisms (SNPs) in 12 RAAS genes as part of the ITMAT-Broad-CARe array. CKD progression phenotypes included decline in estimated glomerular filtration rate (eGFR) over time and the occurrence of a renal disease event, defined as incident end-stage renal disease or halving of eGFR from baseline. Mixed-effects models were used to examine SNP associations with eGFR decline, while Cox proportional hazards models tested SNP associations with renal events. Gene- and pathway-based analyses were conducted using the truncated product method. All analyses were stratified by race, and a Bonferroni correction was applied to adjust for multiple testing. RESULTS: Among white and black participants, eGFR declined an average of 1.2 and 2.3 mL/min/1.73 m(2)/year, respectively, while renal events occurred in a respective 11.5 and 24.9% of participants. We identified strong gene- and pathway-based associations with CKD progression. The AGT and RENBP genes were consistently associated with risk of renal events in separate analyses of white and black participants (both P < 1.00 × 10(-6)). Driven by the significant gene-based findings, the entire RAAS pathway was also associated with renal events in both groups (both P < 1.00 × 10(-6)). No single-marker associations with CKD progression were observed. CONCLUSIONS: The current study provides strong evidence for a role of the RAAS in CKD progression.

Urine neutrophil gelatinase-associated lipocalin and risk of cardiovascular disease and death in CKD: results from the Chronic Renal Insufficiency Cohort (CRIC) Study.

BACKGROUND: Chronic kidney disease is common and is associated with increased cardiovascular disease risk. Currently, markers of renal tubular injury are not used routinely to describe kidney health and little is known about the risk of cardiovascular events and death associated with these biomarkers independent of glomerular filtration-based markers (such as serum creatinine or albuminuria). STUDY DESIGN: Cohort study, CRIC (Chronic Renal Insufficiency Cohort) Study. SETTING & PARTICIPANTS: 3,386 participants with estimated glomerular filtration rate of 20 to 70mL/min/1.73m(2) enrolled from June 2003 through August 2008. PREDICTOR: Urine neutrophil gelatinase-associated lipocalin (NGAL) concentration. OUTCOMES: Adjudicated heart failure event, ischemic atherosclerotic event (myocardial infarction, ischemic stroke, or peripheral artery disease), and death through March 2011. MEASUREMENTS: Urine NGAL measured at baseline with a 2-step assay using chemiluminescent microparticle immunoassay technology on an ARCHITECT i2000SR (Abbott Laboratories). RESULTS: There were 428 heart failure events (during 16,383 person-years of follow-up), 361 ischemic atherosclerotic events (during 16,584 person-years of follow-up), and 522 deaths (during 18,214 person-years of follow-up). In Cox regression models adjusted for estimated glomerular filtration rate, albuminuria, demographics, traditional cardiovascular disease risk factors, and cardiac medications, higher urine NGAL levels remained associated independently with ischemic atherosclerotic events (adjusted HR for the highest [>49.5ng/mL] vs lowest [≤6.9ng/mL] quintile, 1.83 [95% CI, 1.20-2.81]; HR per 0.1-unit increase in log urine NGAL, 1.012 [95% CI, 1.001-1.023]), but not heart failure events or deaths. LIMITATIONS: Urine NGAL was measured only once. CONCLUSIONS: Among patients with chronic kidney disease, urine levels of NGAL, a marker of renal tubular injury, were associated independently with future ischemic atherosclerotic events, but not with heart failure events or deaths.

Race modifies the association between adiposity and inflammation in patients with chronic kidney disease: findings from the chronic renal insufficiency cohort study.

OBJECTIVE: The race-specific association of inflammation with adiposity and muscle mass in subjects with chronic kidney disease (CKD) was examined. METHODS: Plasma concentration of interleukin (IL)-1ß, IL-1 receptor antagonist (IL-1RA), IL-6, IL-10, tumor necrosis factor (TNF)-α, TGF-ß, high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and serum albumin was measured in 3,939 Chronic Renal Insufficiency Cohort study participants. Bioelectric impedance analysis was used to determine body fat mass (BFM) and fat-free mass (FFM). RESULTS: Plasma levels of hs-CRP, fibrinogen, IL-1RA, IL-6, and TNF-α increased and serum albumin decreased across the quartiles of body mass index. In multivariable analysis, BFM and FFM were positively associated with hs-CRP, fibrinogen, IL-1ß, IL-1RA, and IL-6. One standard deviation (SD) increase in BFM and FFM was associated with 0.36 (95% confidence interval [CI] = 0.33, 0.39) and 0.26 (95% CI = 0.22, 0.30) SD increase in log-transformed hs-CRP, respectively (P < 0.001). Race stratified analysis showed that the association between biomarkers and BFM and FFM differed by race, with Caucasians, demonstrating a stronger association with markers of inflammation than African Americans. CONCLUSIONS: BFA and FFM are positively associated with markers of inflammation in patients with CKD. Race stratified analysis showed that Caucasians have a stronger association with markers of inflammation compared to African Americans.

APOL1 risk variants, race, and progression of chronic kidney disease.

BACKGROUND: Among patients in the United States with chronic kidney disease, black patients are at increased risk for end-stage renal disease, as compared with white patients. METHODS: In two studies, we examined the effects of variants in the gene encoding apolipoprotein L1 (APOL1) on the progression of chronic kidney disease. In the African American Study of Kidney Disease and Hypertension (AASK), we evaluated 693 black patients with chronic kidney disease attributed to hypertension. In the Chronic Renal Insufficiency Cohort (CRIC) study, we evaluated 2955 white patients and black patients with chronic kidney disease (46% of whom had diabetes) according to whether they had 2 copies of high-risk APOL1 variants (APOL1 high-risk group) or 0 or 1 copy (APOL1 low-risk group). In the AASK study, the primary outcome was a composite of end-stage renal disease or a doubling of the serum creatinine level. In the CRIC study, the primary outcomes were the slope in the estimated glomerular filtration rate (eGFR) and the composite of end-stage renal disease or a reduction of 50% in the eGFR from baseline. RESULTS: In the AASK study, the primary outcome occurred in 58.1% of the patients in the APOL1 high-risk group and in 36.6% of those in the APOL1 low-risk group (hazard ratio in the high-risk group, 1.88; P<0.001). There was no interaction between APOL1 status and trial interventions or the presence of baseline proteinuria. In the CRIC study, black patients in the APOL1 high-risk group had a more rapid decline in the eGFR and a higher risk of the composite renal outcome than did white patients, among those with diabetes and those without diabetes (P<0.001 for all comparisons). CONCLUSIONS: Renal risk variants in APOL1 were associated with the higher rates of end-stage renal disease and progression of chronic kidney disease that were observed in black patients as compared with white patients, regardless of diabetes status. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others.).

A longitudinal study of left ventricular function and structure from CKD to ESRD: the CRIC study.

BACKGROUND AND OBJECTIVES: Abnormal left ventricular structure and function are associated with increased risk of adverse outcomes among patients with CKD and ESRD. A better understanding of changes in left ventricular mass and ejection fraction during the transition from CKD to ESRD may provide important insights to opportunities to improve cardiac outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a longitudinal study of a subset of participants of the Chronic Renal Insufficiency Cohort who were enrolled from 2003 to 2007 and followed through January of 2011. Participants were included if they had serial echocardiograms performed at advanced CKD (defined as estimated GFR<20 ml/min per 1.73 m(2)) and again after ESRD (defined as need for hemodialysis or peritoneal dialysis). RESULTS: A total of 190 participants (44% female, 66% black) had echocardiograms during advanced CKD and after ESRD. Mean (SD) estimated GFR at advanced CKD was 16.9 (3.5) ml/min per 1.73 m(2). Mean (SD) time between the advanced CKD echocardiogram and ESRD echocardiogram was 2.0 (1.0) years. There was no significant change in left ventricular mass index (62.3-59.5 g/m(2.7), P=0.10) between advanced CKD and ESRD; however, ejection fraction significantly decreased (53%-50%, P=0.002). Interactions for age, race, dialysis modality, and diabetes status were not significant (P>0.05). CONCLUSIONS: Mean left ventricular mass index did not change significantly from advanced CKD to ESRD; however, ejection fraction declined during this transition period. Although left ventricular mass index is fixed by advanced stages of CKD, ejection fraction decline during more advanced stages of CKD may be an important contributor to cardiovascular disease and mortality after dialysis.

Urine neutrophil gelatinase-associated lipocalin levels do not improve risk prediction of progressive chronic kidney disease.

Novel biomarkers may improve our ability to predict which patients with chronic kidney disease (CKD) are at higher risk for progressive loss of renal function. Here, we assessed the performance of urine neutrophil gelatinase-associated lipocalin (NGAL) for outcome prediction in a diverse cohort of 3386 patients with CKD in the Chronic Renal Insufficiency Cohort study. In this cohort, the baseline mean estimated glomerular filtration rate (eGFR) was 42.4 ml/min per 1.73 m(2), the median 24-h urine protein was 0.2 g/day, and the median urine NGAL concentration was 17.2 ng/ml. Over an average follow-up of 3.2 years, there were 689 cases in which the eGFR was decreased by half or incident end-stage renal disease developed. Even after accounting for eGFR, proteinuria, and other known CKD progression risk factors, urine NGAL remained a significant independent risk factor (Cox model hazard ratio 1.70 highest to lowest quartile). The association between baseline urine NGAL levels and risk of CKD progression was strongest in the first 2 years of biomarker measurement. Within this time frame, adding urine NGAL to a model that included eGFR, proteinuria, and other CKD progression risk factors led to net reclassification improvement of 24.7%, but the C-statistic remained nearly identical. Thus, while urine NGAL was an independent risk factor of progression among patients with established CKD of diverse etiology, it did not substantially improve prediction of outcome events.

Risk factors for coronary artery calcium among patients with chronic kidney disease (from the Chronic Renal Insufficiency Cohort Study).

Cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD). We examined the cross-sectional association between novel risk factors and coronary artery calcium (CAC) measured using electron beam computed tomography or multidetector computed tomography among 2,018 patients with CKD. Using the total Agatston scores, the participants were classified as having no (0), moderate (>0-100), or high (>100) CAC. After adjustment for age, gender, race, study sites, cigarette smoking, previous cardiovascular disease, hypertension, and diabetes, the use of lipid-lowering drugs, body mass index, waist circumference, and cystatin C, several novel risk factors were significantly associated with high CAC. For example, the odds ratios of high CAC associated with 1 SD greater level of risk factors were 1.20 (95% confidence interval 1.04 to 1.38) for serum calcium, 1.21 (95% confidence interval 1.04 to 1.41) for serum phosphate, 0.83 (95% confidence interval 0.71 to 0.97) for log (total parathyroid hormone), 1.21 (95% confidence interval 1.03 to 1.43) for log (homeostasis model assessment-insulin resistance), and 1.23 (95% confidence interval 1.04 to 1.45) for hemoglobin A1c. Additionally, the multivariate-adjusted odds ratio for 1 SD greater level of cystatin C was 1.31 (95% confidence interval 1.14 to 1.50). Serum high-sensitive C-reactive protein, interleukin-6, tumor necrosis factor-α, and homocysteine were not statistically significantly associated with high CAC. In conclusion, these data indicate that abnormal calcium and phosphate metabolism, insulin resistance, and declining kidney function are associated with the prevalence of high CAC, independent of the traditional risk factors in patients with CKD. Additional studies are warranted to examine the causal effect of these risk factors on CAC in patients with CKD.

Recruitment of Hispanics into an observational study of chronic kidney disease: the Hispanic Chronic Renal Insufficiency Cohort Study experience.

Despite the large burden of chronic kidney disease (CKD) in Hispanics, this population has been underrepresented in research studies. We describe the recruitment strategies employed by the Hispanic Chronic Renal Insufficiency Cohort Study, which led to the successful enrollment of a large population of Hispanic adults with CKD into a prospective observational cohort study. Recruitment efforts by bilingual staff focused on community clinics with Hispanic providers in high-density Hispanic neighborhoods in Chicago, academic medical centers, and private nephrology practices. Methods of publicizing the study included church meetings, local Hispanic print media, Spanish television and radio stations, and local health fairs. From October 2005 to July 2008, we recruited 327 Hispanics aged 21-74 years with mild-to-moderate CKD as determined by age-specific estimated glomerular filtration rate (eGFR). Of 716 individuals completing a screening visit, 49% did not meet eGFR inclusion criteria and 46% completed a baseline visit. The mean age at enrollment was 57.1 and 67.1% of participants were male. Approximately 75% of enrolled individuals were Mexican American, 15% Puerto Rican, and 10% had other Latin American ancestry. Eighty two percent of participants were Spanish-speakers. Community-based and academic primary care clinics yielded the highest percentage of participants screened (45.9% and 22.4%) and enrolled (38.2% and 24.5%). However, academic and community-based specialty clinics achieved the highest enrollment yield from individuals screened (61.9% to 71.4%). A strategy focused on primary care and nephrology clinics and the use of bilingual recruiters allowed us to overcome barriers to the recruitment of Hispanics with CKD.

CKD in Hispanics: Baseline characteristics from the CRIC (Chronic Renal Insufficiency Cohort) and Hispanic-CRIC Studies.

BACKGROUND: Little is known regarding chronic kidney disease (CKD) in Hispanics. We compared baseline characteristics of Hispanic participants in the Chronic Renal Insufficiency Cohort (CRIC) and Hispanic-CRIC (H-CRIC) Studies with non-Hispanic CRIC participants. STUDY DESIGN: Cross-sectional analysis. SETTING & PARTICIPANTS: Participants were aged 21-74 years with CKD using age-based estimated glomerular filtration rate (eGFR) at enrollment into the CRIC/H-CRIC Studies. H-CRIC included Hispanics recruited at the University of Illinois in 2005-2008, whereas CRIC included Hispanics and non-Hispanics recruited at 7 clinical centers in 2003-2007. FACTOR: Race/ethnicity. OUTCOMES: Blood pressure, angiotensin-converting enzyme (ACE)-inhibitor/angiotensin receptor blocker (ARB) use, and CKD-associated complications. MEASUREMENTS: Demographic characteristics, laboratory data, blood pressure, and medications were assessed using standard techniques and protocols. RESULTS: Of H-CRIC/CRIC participants, 497 were Hispanic, 1,650 were non-Hispanic black, and 1,638 were non-Hispanic white. Low income and educational attainment were nearly twice as prevalent in Hispanics compared with non-Hispanics (P < 0.01). Hispanics had self-reported diabetes (67%) more frequently than non-Hispanic blacks (51%) and whites (40%; P < 0.01). Blood pressure >130/80 mm Hg was more common in Hispanics (62%) than blacks (57%) and whites (35%; P < 0.05), and abnormalities in hematologic, metabolic, and bone metabolism parameters were more prevalent in Hispanics (P < 0.05), even after stratifying by entry eGFR. Hispanics had the lowest use of ACE inhibitors/ARBs among the high-risk subgroups, including participants with diabetes, proteinuria, and blood pressure >130/80 mm Hg. Mean eGFR was lower in Hispanics (39.6 mL/min/1.73 m(2)) than in blacks (43.7 mL/min/1.73 m(2)) and whites (46.2 mL/min/1.73 m(2)), whereas median proteinuria was higher in Hispanics (protein excretion, 0.72 g/d) than in blacks (0.24 g/d) and whites (0.12 g/d; P < 0.01). LIMITATIONS: Generalizability; observed associations limited by residual bias and confounding. CONCLUSIONS: Hispanics with CKD in the CRIC/H-CRIC Studies are disproportionately burdened with lower socioeconomic status, more frequent diabetes mellitus, less ACE-inhibitor/ARB use, worse blood pressure control, and more severe CKD and associated complications than their non-Hispanic counterparts.

Mechanical behavior of bulk amorphous alloys reinforced by ductile particles at cryogenic temperatures.

The mechanical behavior of Zr-based bulk amorphous alloy composites (BAACs) was investigated at 77 K. The 5 vol. % Ta-BAAC maintained large plastic strains of approximately 13% with a 16% strength increase, when compared with that at 298 K. The interaction between shear bands and particles shows that shear extension in particles has limited penetration, and shear bands build up around particles. In addition to on the failure surface of the amorphous matrix, molten characteristics were also found on the surface of sheared particles. Pair distribution function studies were performed to understand the mechanical behavior.