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1.  Association of malnutrition–inflammation complex and responsiveness to erythropoiesis-stimulating agents in long-term hemodialysis patients 
Nephrology Dialysis Transplantation  2012;28(7):1936-1945.
Protein-energy wasting, inflammation and refractory anemia are common in long-term hemodialysis patients. A decreased responsiveness to erythropoiesis-stimulating agents (ESA) is often the cause of the refractory anemia. We hypothesized that the malnutrition–inflammation complex is an independent predictor of decreased responsiveness to ESAs in hemodialysis patients.
This cohort study of 754 hemodialysis patients was examined for an association between inflammatory and nutritional markers, including the malnutrition–inflammation score (MIS) and responsiveness to ESA. Cubic spline models were fitted to verify found associations.
The mean (±SD) age of patients was 54 ± 15 years, 53% were diabetic and 32% blacks. MIS was worse in the highest quartile of ESAs responsiveness index (ERI, ESA dose divided by hemoglobin) when compared with 1st quartile (6.5 ± 4.5 versus 4.4 ± 3.4; P < 0.001). Both C-reactive protein (log CRP) (β = 0.19) and interleukin-6 (log IL-6) (β = 0.32) were strong and independent predictors of ERI using multivariate linear regression. Serum albumin (β = −0.30) and prealbumin levels (β = −0.14) were inversely associated with ERI. Each 1 SD higher MIS, higher CRP and lower albumin were associated with 86, 44 and 97% higher likelihood of having highest versus three lowest ERI quartiles in fully adjusted models [odds ratio (and 95% confidence interval) of 1.86 (1.31–2.85), 1.44 (1.08–1.92) and 1.97 (1.41–2.78)], respectively. Cubic splines confirmed the continuous and incremental nature of these associations.
Malnutrition–inflammation complex is an incremental predictor of poor responsiveness to ESAs in hemodialysis patients. Further studies are needed to assess whether modulating inflammatory or nutritional processes can improve anemia management.
PMCID: PMC3707522  PMID: 23045431
erythropoietin-stimulating agent (ESA) therapy; hemoglobin; inflammatory marker; malnutrition–inflammation complex; responsiveness to ESAs
2.  Long-Term Supplementation With a Cystine-Based Antioxidant Delays Loss of Muscle Mass in Aging 
Oxidative stress increases with age and is postulated to be a major causal factor for sarcopenia in aging. Here, we examined whether the administration of a cystine-based antioxidant (F1) can alleviate/delay age-specific changes in skeletal muscles. C57BL6 male mice aged 17 months (middle aged) were fed with normal diet with or without supplementation of F1 (3mg/kg food) for 6 months. Compared with young (5 months old) mice old mice exhibited increased markers of oxidative stress, inflammation, and muscle cell apoptosis and decreased muscle weight. These age-related changes were further associated with inactivation of adenosine-5′-monophosphate–activated protein kinase (AMPK), increased lipogenesis, activation of c-Jun NH2-terminal kinase, and decreased expression of Delta 1, phospho-Akt, and proliferating cell nuclear antigen in aged skeletal muscle. Such alterations were significantly prevented by F1. These results demonstrate the beneficial effects of F1 to attenuate loss of muscle mass associated with aging.
PMCID: PMC3674717  PMID: 23459206
Antioxidant; Mice; Muscle cell apoptosis; Oxidative stress; Sarcopenia.
3.  What should be the blood pressure target for patients with chronic kidney disease? 
Current opinion in cardiology  2013;28(4):10.1097/HCO.0b013e32836208c2.
Purpose of review
Persons with chronic kidney disease (CKD) exhibit a disproportionate burden of elevated blood pressure (BP) with a high prevalence of premature end-stage renal disease and cardiovascular events.
Recent findings
Results of recent randomized controlled clinical trials suggest that most patients with reduced estimated glomerular filtration rate (eGFR) and hypertension experience optimal clinical outcomes when SBP is less than 140 mmHg and DBP is less than 90 mmHg. The benefit of additional lowering of SBP to less than 130 mmHg and DBP to less than 80 mmHg remains controversial, and appears to be of most benefit to the subset of CKD patients with proteinuria (>300 mg/day). The combination of a diuretic and an angiotensin receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEI) has demonstrated particular promise in patients with reduced eGFR and proteinuria.
A practical approach in clinical practice for the treatment of elevated BP in persons with CKD is to achieve a BP less than 140/90 mmHg with a combination of diuretic and an ARB or ACEI. Consideration for a lower BP goal and other therapeutic and nontherapeutic interventions can be made based on the cause of CKD, presence of proteinuria, or other coexisting medical conditions.
PMCID: PMC3811129  PMID: 23736818
chronic kidney disease; high blood pressure; hypertension
4.  Historically Black Medical Schools: Addressing the Minority Health Professional Pipeline and the Public Mission of Care For Vulnerable Populations 
Substantial changes in not only access to care, cost, and quality of care, but also health professions education are needed to ensure effective national healthcare reform. Since the actionable determinants of health such as personal beliefs and behaviors, socioeconomic factors, and the environment disproportionately affect the poor (and often racial/ethnic minorities), many have suggested that focusing efforts on this population will both directly and indirectly improve the overall health of the nation. Key to the success of such strategies are the ongoing efforts by historically black medical schools (HBMSs) as well as other minority serving medical and health professional schools, who produce a disproportionate percentage of the high-quality and diverse health professionals that are dedicated to maintaining the health of an increasingly diverse nation. Despite their public mission, HBMSs receive limited public support threatening their ability to not only meet the increasing minority health workforce needs but to even sustain their existing contributions. Substantial changes in health education policy and funding are needed to ensure HBMSs as well as other minority-serving medical and health professional schools can continue to produce the diverse, high-quality health professional workforce necessary to maintain the health of an increasingly diverse nation. We explore several model initiatives including focused partnerships with legislative and business leaders that are urgently needed to ensure the ability of HBMSs to maintain their legacy of providing compassionate, quality care to the communities in greatest need.
PMCID: PMC3739050  PMID: 19806842
historically black colleges and universities; minority; health disparities
5.  Follistatin promotes adipocyte differentiation, browning, and energy metabolism[S] 
Journal of Lipid Research  2014;55(3):375-384.
Follistatin (Fst) functions to bind and neutralize the activity of members of the transforming growth factor-β superfamily. Fst has a well-established role in skeletal muscle, but we detected significant Fst expression levels in interscapular brown and subcutaneous white adipose tissue, and further investigated its role in adipocyte biology. Fst expression was induced during adipogenic differentiation of mouse brown preadipocytes and mouse embryonic fibroblasts (MEFs) as well as in cold-induced brown adipose tissue from mice. In differentiated MEFs from Fst KO mice, the induction of brown adipocyte proteins including uncoupling protein 1, PR domain containing 16, and PPAR gamma coactivator-1α was attenuated, but could be rescued by treatment with recombinant FST. Furthermore, Fst enhanced thermogenic gene expression in differentiated mouse brown adipocytes and MEF cultures from both WT and Fst KO groups, suggesting that Fst produced by adipocytes may act in a paracrine manner. Our microarray gene expression profiling of WT and Fst KO MEFs during adipogenic differentiation identified several genes implicated in lipid and energy metabolism that were significantly downregulated in Fst KO MEFs. Furthermore, Fst treatment significantly increases cellular respiration in Fst-deficient cells. Our results implicate a novel role of Fst in the induction of brown adipocyte character and regulation of energy metabolism.
PMCID: PMC3934723  PMID: 24443561
mouse embryonic fibroblast; myostatin; brown fat; energy expenditure; uncoupling protein 1; mitochondria
6.  Reasons for the lack of salutary effects of cholesterol lowering interventions in ESRD populations 
Blood purification  2013;35(1-3):31-36.
Cardiovascular disease (CVD) is the main cause of premature death in patients with chronic kidney disease (CKD). The underlying mechanisms of CVD in patients with mild to moderate CKD are different from those with end-stage renal disease (ESRD). While serum cholesterol is frequently elevated and contributes to atherosclerosis in many CKD patients particularly those with nephrotic proteinuria, it is usually normal, even subnormal in most ESRD patients receiving hemodialysis. CVD in the ESRD population is primarily driven by oxidative stress, inflammation, accumulation of the oxidation-prone intermediate density lipoproteins (IDL), chylomicron remnants and small dense LDL particles as well as HDL deficiency and dysfunction, hypertension, vascular calcification, and arrhythmias. Only a minority of hemodialysis patients have hypercholesterolemia which is most likely due to genetic or unrelated factors. In addition due to peritoneal losses of proteins which simulate nephrotic syndrome, peritoneal dialysis patients often exhibit hypercholesterolemia. Clearly when present, hypercholesterolemia contributes to CVD in CKD and ESRD population and justifies cholesterol lowering therapy. However the majority of ESRD patients and a subpopulation of CKD patients with minimal proteinuria have normal or subnormal serum cholesterol levels and do not benefit from and can be potentially harmed by statin therapy. In fact the lack of efficacy of statins in hemodialysis patients has been demonstrated in several randomized clinical trials. This review is intended to provide an overview of the mechanisms responsible for the failure of statins to reduce cardiovascular morbidity and mortality in most ESRD patients and to advocate the adoption of individualized care principal in the management of dyslipidemia in this population.
PMCID: PMC3595172  PMID: 23343544
Statins; lipid disorders; cardiovascular disease; progression of kidney disease; hemodialysis; nephrotic syndrome
7.  1,25(OH)2vitamin D3 Enhances Myogenic Differentiation by Modulating the Expression of Key Angiogenic Growth factors and Angiogenic Inhibitors in C2C12 Skeletal Muscle Cells 
Vitamin D is mostly recognized for its regulation of calcium homeostasis in relation to the intestine, kidney, and bone. Although clinical studies have linked vitamin D with increased muscle function and strength, little is known of its underlying molecular mechanism. We recently demonstrated that 1,25-D3 exerts a direct pro-myogenic effect on skeletal muscle cells; this has provoked our investigation of 1,25-D’s effect on angiogenesis, a vital process for new capillary development and tissue repair. In this study, we examined the mechanism by which 1,25-D3 modulates key angiogenic growth factors and angiogenic inhibitors. C2C12 myoblasts were incubated with 100 nM 1,25-D3 or placebo for 1, 4 and 10 days. At the end of the respective incubation time, total RNA was isolated for PCR arrays and for qRT-PCR. Total proteins were isolated for western blots and proteome profiler arrays. The addition of 1,25-D3 to C2C12 myoblasts increased VEGFa and FGF-1: two pro-angiogenic growth factors that promote neo-vascularization and tissue regeneration, and decreased FGF-2 and TIMP-3: two myogenic and/or angiogenic inhibitors. Our previous study demonstrated that 1,25-D3 altered IGF-I/II expression, consistent with the observed changes in VEGFa and FGF-2 expression. These results extend our previous findings and demonstrate the modulation of angiogenesis which may be an additional mechanism by which 1,25-D3 promotes myogenesis. This study supports the mechanistic rationale for assessing the administration of vitamin D and/or vitamin D analogues to treat select muscle disorders and may also provide an alternative solution for therapies that directly manipulate VEGF and FGF’s to promote angiogenesis.
PMCID: PMC3513642  PMID: 22982629
9.  Donor Race and Outcomes in Kidney Transplant Recipients 
Clinical transplantation  2012;27(1):37-51.
African Americans are at greater risk to reach end stage renal disease and this risk may carry over in a kidney transplant recipient after kidney transplantation.
Linking the 5-year patient data of a large dialysis organization to the Scientific Registry of Transplant Recipients, we identified 13,692 hemodialysis patients who underwent first kidney transplantation. Mortality or graft failure and delayed graft function (DGF) risks were estimated by Cox regression (hazard ratio [HR] and 95% CI) and logistic regression, respectively.
Patients were 48±14 years old and included 39% women and 26% diabetics. After adjusting for several relevant clinical and transplant-related variables, African American donor race was associated with higher all-cause mortality, with hazard ratios of 1.39 (1.09–1.78) for all-cause mortality, 1.80 (1.17–2.76) for cardiovascular mortality, 1.30 (1.03–1.64) for death-censored graft loss and 1.31 (1.10–1.57) for combined outcome over the 6-year observation period. In the non-African American recipient sub-cohort, but not in the African American recipient sub-cohort, African American donor race was associated with higher risk of death-censored graft loss (2.24(1.44–3.49)) in our fully adjusted model.
African American donor race was associated with increased all-cause and cardiovascular mortality and graft loss.
PMCID: PMC3593049  PMID: 22830989
Donor race/ethnicity; kidney transplantation; malnutrition-inflammation complex; mortality; cardiovascular death; graft failure; delayed graft function
10.  Long-term Effects of Renin-Angiotensin System–Blocking Therapy and a Low Blood Pressure Goal on Progression of Hypertensive Chronic Kidney Disease in African Americans 
Archives of internal medicine  2008;168(8):10.1001/archinte.168.8.832.
Antihypertensive drugs that block the renin-angiotensin system (angiotensin-converting enzyme inhibitors [ACEIs] or angiotensin receptor blockers) are recommended for patients with chronic kidney disease (CKD). A low blood pressure (BP) goal (BP, <130/80 mm Hg) is also recommended. The objective of this study was to determine the long-term effects of currently recommended BP therapy in 1094 African Americans with hypertensive CKD.
Multicenter cohort study following a randomized trial. Participants were 1094 African Americans with hypertensive renal disease (glomerular filtration rate, 20–65 mL/min/1.73 m2). Following a 3×2-factorial trial (1995–2001) that tested 3 drugs used as initial antihypertensive therapy (ACEIs, calcium channel blockers, and β-blockers) and 2 levels of BP control (usual and low), we conducted a cohort study (2002–2007) in which participants were treated with ACEIs to a BP lower than 130/80 mm Hg. The outcome measures were a composite of doubling of the serum creatinine level, end-stage renal disease, or death.
During each year of the cohort study, the annual use of an ACEI or an angiotensin receptor blocker ranged from 83.7% to 89.0% (vs 38.5% to 49.8% during the trial). The mean BP in the cohort study was 133/78 mm Hg (vs 136/82 mm Hg in the trial). Overall, 567 participants experienced the primary outcome; the 10-year cumulative incidence rate was 53.9%. Of 576 participants with at least 7 years of follow-up, 33.5% experienced a slow decline in kidney function (mean annual decline in the estimated glomerular filtration rate, <1 mL/min/1.73 m2).
Despite the benefits of renin-angiotensin system–blocking therapy on CKD progression, most African Americans with hypertensive CKD who are treated with currently recommended BP therapy continue to progress during the long term.
PMCID: PMC3870204  PMID: 18443258
11.  Anti-Inflammatory and Anti-Oxidative Nutrition in Hypoalbuminemic Dialysis Patients (AIONID) study: results of the pilot-feasibility, double-blind, randomized, placebo-controlled trial 
Low serum albumin is common and associated with protein-energy wasting, inflammation, and poor outcomes in maintenance hemodialysis (MHD) patients. We hypothesized that in-center (in dialysis clinic) provision of high-protein oral nutrition supplements (ONS) tailored for MHD patients combined with anti-oxidants and anti-inflammatory ingredients with or without an anti-inflammatory appetite stimulator (pentoxifylline, PTX) is well tolerated and can improve serum albumin concentration.
Between January 2008 and June 2010, 84 adult hypoalbuminemic (albumin <4.0 g/dL) MHD outpatients were double-blindly randomized to receive 16 weeks of interventions including ONS, PTX, ONS with PTX, or placebos. Nutritional and inflammatory markers were compared between the four groups.
Out of 84 subjects (mean ± SD; age, 59 ± 12 years; vintage, 34 ± 34 months), 32 % were Blacks, 54 % females, and 68 % diabetics. ONS, PTX, ONS plus PTX, and placebo were associated with an average change in serum albumin of +0.21 (P = 0.004), +0.14 (P = 0.008), +0.18 (P = 0.001), and +0.03 g/dL (P = 0.59), respectively. No related serious adverse events were observed. In a predetermined intention-to-treat regression analysis modeling post-trial serum albumin as a function of pre-trial albumin and the three different interventions (ref = placebo), only ONS without PTX was associated with a significant albumin rise (+0.17 ± 0.07 g/dL, P = 0.018).
In this pilot-feasibility, 2 × 2 factorial, placebo-controlled trial, daily intake of a CKD-specific high-protein ONS with anti-inflammatory and anti-oxidative ingredients for up to 16 weeks was well tolerated and associated with slight but significant increase in serum albumin levels. Larger long-term controlled trials to examine hard outcomes are indicated.
Electronic supplementary material
The online version of this article (doi:10.1007/s13539-013-0115-9) contains supplementary material.
PMCID: PMC3830006  PMID: 24052226
Albumin; Hypoalbuminemia; Inflammation; Protein intake; Hemodialysis; Oral nutrition supplements; Anti-oxidant ingredients; Anti-inflammatory ingredients
12.  Patient Care Staffing Levels and Facility Characteristics in U.S. Hemodialysis Facilities 
Higher numbers of registered nurses per patient have been associated with improved patient outcomes in acute care facilities. Variation and associations of patient-care staffing levels and hemodialysis facility characteristics have not been previously examined.
Study Design
Cross-sectional study using Poisson regression to examine associations betwee patient-care staffing levels and hemodialysis facility characteristics.
Setting & Participants
4,800 U.S. hemodialysis facilities in the 2009 CMS ESRD Annual Facility Survey (CMS-2744), USRDS.
Facility characteristics, including profit status, freestanding status, chain affiliatio and geographic region, adjusted for facility size, capacity, functional type, and urbanicity.
Patient care staffing levels, including ratios of Registered Nurses (RN), Licensed Practical Nurses (LPN), Patient Care Technicians (PCT), composite staff (RN+LPN+PCT), Social Workers, and Dietitians to in-center hemodialysis patients.
After adjusting for background facility characteristics, the ratios of RNs and LPNs to patients were 35% (p<0.001) and 42% (p<0.001) lower, but the PCT-to-patient ratio was 16% (p<0.001) higher in for-profit facilities than those in nonprofit facilities (Rate ratio, 0.65, 95%CI, 0.63–0.68; 0.58, 0.51–0.65; 1.16, 1.12–1.19; respectively). Regionally, compared to the Northeast, the adjusted RN-to-patient ratio was 14% (p< 0.001) lower in the Midwest, 25% (p< 0.001) lower in the South, and 18% (p< 0.001) lower in the West. Even after additional adjustments, the large for-profit chains had significantly lower RN and LPN ratios than the largest nonprofit chain, but a significantly higher PCT-to-patient ratio. The overall composite staffing levels were also lower in for-profit and chain-affiliated facilities. The patterns hold when the hospital-based units were excluded.
Nursing hours were not available.
The significant variation in patient-care staffing levels and its associations with facility characteristics warrants inclusion in future large-scale hemodialysis outcomes studies. ESRD networks and hemodialysis facilities should attend to quality assurance and performance improvement initiatives that maximize licensed nurse-staffing levels in hemodialysis facilities.
PMCID: PMC3840051  PMID: 23810689
USRDS; in-center hemodialysis; CMS ESRD Facility survey; staffing ratios; profit; region
13.  Baseline Predictors of Renal Disease Progression in the African American Study of Hypertension and Kidney Disease 
Journal of the American Society of Nephrology : JASN  2006;17(10):10.1681/ASN.2005101101.
Patients with chronic kidney disease have an increased risk for progression to ESRD. The purpose of this study was to examine factors that predict increased risk for adverse renal outcomes. Cox regression was performed to assess the potential of 38 baseline risk factors to predict the clinical renal composite outcome of 50% or 25-ml/min per 1.73 m2 GFR decline or ESRD among 1094 black patients with hypertensive nephrosclerosis (GFR 20 to 65 ml/min per 1.73 m2). Patients were trial participants who had been randomly assigned to one of two BP goals and to one of three antihypertensive regimens and followed for a range of 3 to 6.4 yr. In unadjusted and adjusted analyses, baseline proteinuria was consistently associated with an increased risk for adverse renal outcomes, even at low levels of proteinuria. The relationship of proteinuria with adverse renal outcomes also was evident in analyses that were stratified by level of GFR, which itself was associated with adverse renal outcomes but only at levels <40 ml/min. Other factors that were significantly associated with increased renal events after adjustment for baseline GFR, age, and gender, both with and without adjustment for baseline proteinuria, included serum creatinine, urea nitrogen, and phosphorus. In black patients with hypertensive nephrosclerosis, increased proteinuria, reduced GFR, and elevated levels of serum creatinine, urea nitrogen and phosphorus were directly associated with adverse clinical renal events. These findings identify a subset of this high-risk population that might benefit from even more aggressive treatment.
PMCID: PMC3833081  PMID: 16959828
14.  Vitamin D and Cardiovascular Disease: Potential Role in Health Disparities 
Cardiovascular disease (CVD), which includes coronary artery disease and stroke, is the leading cause of mortality in the nation. Excess CVD morbidity and premature mortality in the African American community is one of the most striking examples of racial/ethnic disparities in health outcomes. African Americans also suffer from increased rates of hypovitaminosis D, which has emerged as an independent risk factor for all-cause and cardiovascular mortality. This overview examines the potential role of hypovitaminosis D as a contributor to racial and ethnic disparities in cardiovascular disease (CVD). We review the epidemiology of vitamin D and CVD in African Americans and the emerging biological roles of vitamin D in key CVD signaling pathways that may contribute to the epidemiological findings and provide the foundation for future therapeutic strategies for reducing health disparities.
PMCID: PMC3417128  PMID: 22102304
VDR; CVD; PAI; Wrch-1; Rho; Fst
15.  Chronic kidney disease, hypovitaminosis D, and mortality in the United States 
Kidney international  2009;76(9):977-983.
Low serum 25-hydroxy vitamin D (25OHD) predicts a higher cardiovascular risk in the general population. Because patients with chronic kidney disease are more likely to have low serum 25OHD, we determined the relationship between hypovitaminosis D and death in this group. Analysis was done using a cohort composed of 3011 patients from the Third National Health and Nutrition Examination Survey who had chronic kidney disease but were not on dialysis and who had a mean follow-up of 9 years. In analyses adjusted for demographics, cardiovascular risk factors, serum phosphorus, albumin, hemoglobin, stage of chronic kidney disease, albuminuria, and socioeconomic status, individuals with serum 25OHD levels less than 15 ng/ml had an increased risk for all-cause mortality when compared to those with levels over 30 ng/ml. This significantly higher risk for death with low serum 25OHD was evident in 15 of the 23 subgroups. The higher risk for cardiovascular and non-cardiovascular mortality became statistically nonsignificant on multivariable adjustment. The trend for higher mortality in patients with 25OHD levels 15–30 ng/ml was not statistically significant. Our results indicate there is a graded relationship between serum 25OHD and the risk for death among subjects with chronic kidney disease who are not undergoing dialysis. Randomized, controlled trials are needed to conclusively determine whether vitamin D supplementation reduces mortality.
PMCID: PMC3791220  PMID: 19657329
cardiovascular; chronic kidney disease; mortality; non-cardiovascular; vitamin D
16.  The Healthy African American Families (HAAF) Project: From Community-Based Participatory Research To Community-Partnered Participatory Research 
Ethnicity & disease  2010;20(1 0 2):S2-1-8.
During the past two decades, there has been an increased use of community-based participatory research in public health activities, especially as part of efforts to understand health disparities affecting communities of color. This article describes the history and lessons learned of a long-standing community participatory project, Healthy African American Families (HAAF), in Los Angeles, California. HAAF evolved from a partnership formed by a community advisory board, university, and federal health agency to an independent, incorporated community organization that facilitates and brokers research and health promotion activities within its community. HAAF created mechanisms for community education and networks of community relationships and reciprocity through which mutual support, research, and interventions are integrated. These sustained, institutionalized relationships unite resources and both community and scientific expertise in a community-partnered participatory research model to address multiple health problems in the community, including preterm birth, HIV, asthma, depression, and diabetes. The HAAF participatory process builds on existing community resiliency and resources and on centuries of self-help, problem-solving, cooperative action, and community activism within the African American community. HAAF demonstrates how community-partnered participatory research can be a mechanism for directing power, collective action, system change, and social justice in the process of addressing health disparities at the community level.
PMCID: PMC3791221  PMID: 20629240
Community-based Participatory Research; Community-partnered Participatory Research; African American; Family
17.  Vitamin D reduces the expression of collagen and key profibrotic factors by inducing an antifibrotic phenotype in mesenchymal multipotent cells 
The Journal of endocrinology  2008;200(2):207-221.
Hypovitaminosis D is an important public health problem. Serum 25-hydroxyvitamin D (25-OHD) is now recognized as an independent predictor for cardiovascular and related diseases (CVD) as well as other chronic medical conditions. However, the biologic pathways through which these effects are mediated remain poorly understood. We hypothesized that exposing mesenchymal multipotent cells (MMCs) to the active form of vitamin D would increase the expression of selected antifibrotic factors that in turn would ameliorate the progression of chronic diseases. MMCs were primed with 5′-azacytidine to induce a fibrotic phenotype and then treated with active vitamin D (1,25D) or ethanol <0·1% as vehicle in a time course manner (30 min, 1, 5, and 24 h, and for 4 and 7 days). The addition of 1,25D to MMCs promotes: a) increased expression and nuclear translocation of the vitamin D receptor; b) decreased expression of TGFB1 and plasminogen activator inhibitor (SERPINE1), two well-known profibrotic factors; c) decreased expression of collagen I, III and other collagens isoforms; and d) increased expression of several antifibrotic factors such as BMP7 a TGFB1 antagonist, MMP8 a collagen breakdown inducer and follistatin, an inhibitor of the profibrotic factor myostatin. In conclusion, the addition of 1,25D to differentiated MMCs displays a decreased profibrotic signaling pathway and gene expression, leading to decrease in collagen deposition. This study highlights key mechanistic pathways through which vitamin D decreases fibrosis, and provides a rationale for studies to test vitamin D supplementation as a preventive and/or early treatment strategy for CVD and related fibrotic disorders.
PMCID: PMC3787314  PMID: 19036760
18.  Inhibition of apoptotic signaling in spermine-treated vascular smooth muscle cells by a novel glutathione precursor 
Cell biology international  2010;34(5):503-511.
Chronic kidney disease (CKD) is a public health problem, mediated by hemodynamic and non-hemodynamic events including oxidative stress. We investigated the effect of two glutathione (GSH) precursors, N-acetyl-cysteine (NAC) and cystine as the physiologic carrier of cysteine in GSH with added selenomethionine (F1) in preventing spermine (uremic toxin) induced apoptosis in cultured human aortic vascular smooth muscle cells (VSMC). VSMCs exposed to spermine (15 μM) with or without antioxidants (dose 50, 100, 200 and 500 μg/ml) were assessed for apoptosis, c-Jun-NH2-terminal kinase (JNK) activation and inducible nitric oxide synthase (iNOS) induction, and activation of intrinsic pathway signaling. Spermine exposure resulted in activation of JNK and iNOS induction, and apoptosis. NAC and F1 (dose range 50–500 μg/ml) attenuated spermine-induced acceleration of VSMC apoptosis, but only F1 (at 200 and 500 μg/ml) maintained spermine-induced apoptosis at control levels. Spermine-induced JNK activation was prevented by 200 μg/ml of both NAC and F1, while iNOS induction was blocked only by F1. Notably, the adverse effects of spermine on BAX/BCL-2 ratio, cytochrome c release, and caspase activation was fully attenuated by F1. In conclusion, F1 was more effective than NAC in preventing spermine-induced apoptosis and downstream changes in related signal transduction pathways in VSMCs. Further studies are needed to examine the effect of these compounds in preventing CKD-associated vascular disease.
PMCID: PMC3748361  PMID: 20121705
Spermine; Apoptosis; vascular smooth muscle cells; antioxidants; chronic kidney disease
19.  Association Between Lack of Health Insurance and Risk of Death and ESRD: Results From the Kidney Early Evaluation Program (KEEP) 
Uninsured adults in the United States have poor access to health care services and worse health outcomes than insured adults. Little is known about the association between lack of insurance and chronic kidney disease (CKD) progression to end-stage renal disease (ESRD) or death in patients at high risk of kidney disease. We used 2000–2011 data from the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP) to examine this association.
The study population included KEEP participants younger than 65 years. Outcomes were time to ESRD (chronic kidney failure treated by renal replacement therapy) and time to death. Incident ESRD was ascertained by linkage to the US Renal Data System, and vital status, by linkage to the Social Security Administration Death Master File. We used Cox proportional hazard regression to examine the association between insurance and risk of death or ESRD after adjusting for demographic variables.
Of 86,588 participants, 27.8% had no form of insurance, 10.3% had public insurance, and 61.9% had private insurance; 15.0% had CKD (defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 or urine albumin-creatinine ratio ≥30 mg/g), 63.3% had hypertension, and 27.7% had diabetes. Of participants with CKD, 29.3% had no health insurance. Participants without insurance were younger, more likely to be Hispanic and to have 12 or fewer years of education, and less likely to have seen a physician in the past year. After adjustment for demographic characteristics, uninsured KEEP participants were 82% more likely than privately insured participants to die (HR, 1.82; 95% CI, 1.56–2.12; P < 0.001) and 72% more likely to develop ESRD (HR, 1.72; 95% CI, 1.33–2.22; P < 0.001). The association between insurance and outcomes varied by CKD stage.
Lack of insurance is an independent risk factor for early death and ESRD in this population at high risk of kidney disease. Considering the high morbidity and mortality and increasing cost associated with ESRD, access to appropriate health insurance coverage is warranted.
PMCID: PMC3739048  PMID: 23507267
Chronic kidney disease; end-stage renal disease; health insurance; mortality; public health
20.  Story of Stone Soup: A Recipe to Improve Health Disparities 
Ethnicity & disease  2010;20(1 0 2):S2-9-14.
Just as scientific articles are used as a way of sharing knowledge in scientific communities, stories are used as a way of transferring knowledge within African American communities. This article uses the story and metaphor of Stone Soup to illustrate the Healthy African American Families' (HAAF) Community Partnered Participatory Research (CPPR) method of engaging diverse partners to address health issues, such as preterm birth, depression, diabetes, and kidney disease, and to create community-wide change through education, capacity building, resource sharing, and intervention development.
PMCID: PMC3709872  PMID: 20629241
African American; Family; Community Partnered Participatory Research
21.  The Association between Parathyroid Hormone Levels and Hemoglobin in Diabetic and Nondiabetic Participants in the National Kidney Foundation's Kidney Early Evaluation Program 
Cardiorenal Medicine  2013;3(2):120-127.
Both anemia and secondary hyperparathyroidism are reflections of hormonal failure in chronic kidney disease (CKD). While the association of elevated levels of parathyroid hormone (PTH) and anemia has been studied among those with advanced CKD, less is known about this association in mild-to-moderate CKD.
In a cross-sectional analysis, the relationship between PTH and hemoglobin levels was investigated in 10,750 participants in the National Kidney Foundation's Kidney Early Evaluation Program with an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2.
In the unadjusted analysis, higher PTH levels were associated with lower hemoglobin levels. However, after multivariable adjustment for age, race, gender, smoking status, education, cardiovascular disease, diabetes, hypertension, cancer, albuminuria, BMI, baseline eGFR, calcium, and phosphorus, the direction of association changed. As compared to the first PTH quintile, hemoglobin levels were 0.09 g/dl (95% CI: 0.01-0.18), 0.15 g/dl (95% CI: 0.07-0.24), 0.18 g/dl (95% CI: 0.09-0.26), and 0.13 g/dl (95% CI: 0.07-0.25) higher for the second, third, fourth, and fifth quintiles, respectively. Similarly, each standard deviation increase in natural log transformed PTH was associated with a 0.06 g/dl (95% CI: 0.03-0.09, p = 0.0003) increase in hemoglobin. However, a significant effect modification was seen for diabetes (p = 0.0003). Each standard deviation increase in natural log transformed PTH was associated with a 0.10 g/dl (95% CI: 0.054-0.138, p < 0.0001) increase in hemoglobin, while no association was seen among those without diabetes mellitus.
After multivariable adjustment, there was a small positive association between PTH and hemoglobin among diabetics but not among nondiabetics.
PMCID: PMC3721130  PMID: 23922552
Chronic kidney disease; Anemia; Secondary hyperparathyroidism

22.  Physician Utilization, Risk-Factor Control, and CKD Progression Among Participants in the Kidney Early Evaluation Program (KEEP) 
Chronic kidney disease (CKD) is a well-known risk factor for cardiovascular mortality, but little is known about the association between physician utilization and cardiovascular disease risk-factor control in patients with CKD. We used 2005–2010 data from the National Kidney Foundation’s Kidney Early Evaluation Program (KEEP) to examine this association at first and subsequent screenings.
Control of risk factors was defined as control of blood pressure, glycemia, and cholesterol levels. We used multinomial logistic regression to examine the association between participant characteristics and seeing a nephrologist after adjusting for kidney function and paired t tests or McNemar tests to compare characteristics at first and second screenings.
Of 90,009 participants, 61.3% had a primary care physician only, 2.9% had seen a nephrologist, and 15.3% had seen another specialist. The presence of 3 risk factors (hypertension, diabetes, and hypercholesterolemia) increased from 26.8% in participants with CKD stages 1–2 to 31.9% in those with stages 4–5. Target levels of all risk factors were achieved in 7.2% of participants without a physician, 8.3% of those with a primary care physician only, 9.9% of those with a nephrologist, and 10.3% of those with another specialist. Of up to 7,025 participants who met at least one criterion for nephrology consultation at first screening, only 12.3% reported seeing a nephrologist. Insurance coverage was associated strongly with seeing a nephrologist. Of participants who met criteria for nephrology consultation, 406 (5.8%) returned for a second screening, of whom 19.7% saw a nephrologist. The percentage of participants with all risk factors controlled was higher at the second screening (20.9% vs 13.3%).
Control of cardiovascular risk factors is poor in the KEEP population. The percentage of participants seeing a nephrologist is low, although better after the first screening. Identifying communication barriers between nephrologists and primary care physicians may be a new focus for KEEP.
PMCID: PMC3654535  PMID: 22339899
Cardiovascular disease risk factors; chronic kidney disease; nephrologist care; primary care
23.  Survival Disparities within American and Israeli Dialysis Populations: Learning from Similarities and Distinctions across Race and Ethnicity 
Seminars in dialysis  2010;23(6):586-594.
There are counterintuitive but consistent observations that African American maintenance dialysis patients have greater survival despite their less favorable socioeconomic status, high burden of cardiovascular risks including hypertension and diabetes, and excessively high chronic kidney disease prevalence. The fact that such individuals have a number of risk factors for lower survival and yet live longer when undergoing dialysis treatment is puzzling. Similar findings have been made among Israeli maintenance dialysis patients, in that those who are ethnically Arab have higher end-stage renal disease but exhibit greater survival than Jewish Israelis. The juxtaposition of these two situations may provide valuable insights into racial/ethnic-based mechanisms of survival in chronic diseases. Survival advantages of African American dialysis patients may be explained by differences in nutritional status, inflammatory profile, dietary intake habits, body composition, bone and mineral disorders, mental health and coping status, dialysis treatment differences, and genetic differences among other factors. Prospective studies are needed to examine similar models in other countries and to investigate the potential causes of these paradoxes in these societies. Better understanding the roots of racial/ethnic survival differences may help improve outcomes in both patients with chronic kidney disease and other individuals with chronic disease states.
PMCID: PMC3618910  PMID: 21175833
24.  Hypertensive chronic kidney disease in African Americans: Strategies for improving care 
African Americans have a disproportionate burden of chronic kidney disease (CKD), which tends to have an earlier onset and a more rapid progression in this population. Many of the factors responsible for the rapid progression of CKD in African Americans are detectable by screening and are modifiable with prompt therapy.
PMCID: PMC3607200  PMID: 23027732
25.  Racial and Ethnic Differences in Mortality of Hemodialysis Patients: Role of Dietary and Nutritional Status and Inflammation 
American Journal of Nephrology  2011;33(2):157-167.
Racial/ethnic disparities prevail among hemodialysis patients. We hypothesized that significant differences exist between Black and non-Hispanic and Hispanic White hemodialysis patients in nutritional status, dietary intake and inflammation, and that they account for racial survival disparities.
In a 6-year (2001–2007) cohort of 799 hemodialysis patients, we compared diet and surrogates of nutritional-inflammatory status and their mortality-predictabilities between 279 Blacks and 520 Whites using matched and regression analyses and Cox with cubic splines.
In age-, gender- and diabetes-matched analyses, Blacks had higher lean body mass and serum prealbumin, creatinine and homocysteine levels than Whites. In case-mix-adjusted analyses, dietary intakes in Blacks versus Whites were higher in energy (+293 ± 119 cal/day) and fat (+18 ± 5 g/day), but lower in fiber (−2.9 ± 1.3 g/day) than Whites. In both races, higher serum albumin, prealbumin and creatinine were associated with greater survival, whereas CRP and IL-6, but not TNF-α, were associated with increased mortality. The highest (vs. lowest) quartile of IL-6 was associated with a 2.4-fold (95% CI: 1.3–3.8) and 4.1-fold (2.2–7.2) higher death risk in Blacks and Whites, respectively.
Significant racial disparities exist in dietary, nutritional and inflammatory measures, which may contribute to hemodialysis outcome disparities. Testing race-specific dietary and/or anti-inflammatory interventions is indicated.
PMCID: PMC3202917  PMID: 21293117
Black race; Hispanic ethnicity; African Americans; Non-Hispanic White; Nutritional status; Inflammatory markers; Dietary intake; Survival

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