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1.  Expansion of urease- and uricase-containing, indole- and p-cresol-forming and contraction of short chain fatty acid-producing intestinal microbiota in ESRD 
American journal of nephrology  2014;39(3):230-237.
Background
Intestinal microbiome constitutes a symbiotic ecosystem that is essential for health, and changes in its composition/function cause various illnesses. Biochemical milieu shapes the structure and function of the microbiome. Recently we found marked differences in the abundance of numerous bacterial taxa between ESRD and healthy individuals. Influx of urea and uric acid and dietary restriction of fruits and vegetables to prevent hyperkalemia alter ESRD patients’ intestinal milieu. We hypothesized that relative abundances of bacteria possessing urease, uricase, and p-cresol- and indole-producing enzymes is increased, while abundance of bacteria containing enzymes converting dietary fiber to short chain fatty acids (SCFA) is reduced in ESRD.
Methods
Reference sets of bacteria containing genes of interest were compiled to family, and sets of intestinal bacterial families showing differential abundances between 12 healthy and 24 ESRD individuals enrolled in our original study were compiled. Overlap between sets was assessed using hypergeometric distribution tests.
Results
: Among 19 microbial families that were dominant in ESRD patients, 12 possessed urease, 5 possessed uricase, and 4 possessed indole and p-cresol forming enzymes. Among 4 microbial families that were diminished in ESRD patients, 2 possessed butyrate-forming enzymes. Probabilities of these overlapping distributions were <0.05.
Conclusions
ESRD patients exhibited significant expansion of bacterial families possessing urease, uricase, and indole and p-cresol forming enzymes, and contraction of families possessing butyrate-forming enzymes. Given the deleterious effects of indoxyl sulfate, p-cresol sulfate, and urea-derived ammonia, and beneficial actions of SCFA, these changes in intestinal microbial metabolism contribute to uremic toxicity and inflammation.
doi:10.1159/000360010
PMCID: PMC4049264  PMID: 24643131
CKD; hemodialysis; inflammation; uric acid; uremic toxins; microbiome; malnutrition; gastrointestinal
2.  Statin Use and Calcific Uremic Arteriolopathy: A Matched Case-Control Study 
American journal of nephrology  2013;37(4):325-332.
Background
Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is characterized by vascular calcification, thrombosis and intense inflammation. Prior research has shown that statins have anticalcification, antithrombotic and antiinflammatory properties; however, the association between statin use and CUA has not been investigated.
Methods
This matched case-control study included 62 adult maintenance hemodialysis (HD) patients with biopsy-confirmed CUA diagnosed between the years 2002 and 2011 (cases). All cases were hospitalized at the time of diagnosis. Controls (n = 124) were hospitalized maintenance HD patients without CUA (matched to cases by gender and timing of hospitalization). Univariate and multivariable logistic regression models were applied to compute odds ratio (OR) and 95% confidence intervals (CI) for CUA in statin users, and also to examine previously described associations.
Results
The mean age of cases was 58 years. Most were females (68%), and of white race (64%). Statin use was more common in controls than in cases (39 vs. 19%, p < 0.01). Statin use was associated with lower odds of CUA in unadjusted (OR 0.38, 95% CI 0.18–0.79) and adjusted (OR 0.20, 95% CI 0.05–0.88) analyses. Hypercalcemia (OR 2.25, 95% CI 1.14–4.43), hypoalbuminemia (OR 5.73, 95% CI 2.79–11.77), calcitriol use (OR 5.69, 95% CI 1.02–31.77) and warfarin use (OR 4.30, 95% CI 1.57–11.74) were positively associated with CUA in adjusted analyses whereas paricalcitol and doxercalciferol were not (OR 1.33, 95% CI 0.54–3.27).
Conclusion
Statin use may be negatively associated with odds of CUA. Further large prospective studies with attention to potential confounders are needed to confirm these findings.
doi:10.1159/000348806
PMCID: PMC4110510  PMID: 23548843
Calcific uremic arteriolopathy; Calciphylaxis; Case control; Statin; Vitamin D
3.  Oral activated charcoal adsorbent (AST-120) ameliorates CKD-induced intestinal epithelial barrier disruption 
American journal of nephrology  2013;37(6):518-525.
Back ground
CKD impairs intestinal barrier function which by allowing influx of noxious products causes systemic inflammation. We have recently shown that intestinal barrier dysfunction in CKD is due to degradation of epithelial tight junction (TJ) which is, in part, mediated by influx of urea and its conversion to ammonia by microbial urease. We hypothesized that by adsorbing urea and urea-derived ammonia, oral activated charcoal (AST-120) may ameliorate CKD-induced intestinal epithelial barrier disruption and systemic inflammation.
Methods
Rats were randomized to the CKD or control groups. The CKD group was fed a chow containing 0.7% adenine for 2 weeks. They were then randomized to receive a chow with or without AST-120 (4 g/kg/day) for 2 weeks. Rats consuming regular diet served as controls. Animals were then euthanized, colons were removed and processed for Western blot and immunohistology and plasma was used to measure endotoxin, and oxidative and inflammatory markers.
Results
Compared with the controls the untreated CKD rats showed elevated plasma endotoxin, IL-6, TNFα, MCP-1, CINC-3, L-selectin, ICAM-1, and malondialdehyde, and depletions of colonic epithelial TJ proteins; claudin-1, occludin, and ZO1. Administration of AST-120 resulted in partial restoration of the epithelial TJ proteins and reduction in plasma endotoxin and markers of oxidative stress and inflammation.
Conclusions
CKD animals exhibited depletion of the key protein constituents of the colonic epithelial TJ which was associated with systemic inflammation, oxidative stress and endotoxemia. Administration of AST-120 attenuated uremia-induced disruption of colonic epithelial TJ and the associated endotoxemia, oxidative stress and inflammation.
doi:10.1159/000351171
PMCID: PMC3777856  PMID: 23689670
Epithelial tight junction; Endotoxin; activated charcoal; ESRD; uremia
5.  Seasonal Maintenance of Influenza Vaccine-Induced Antibody Response in Kidney Transplant Recipients 
American journal of nephrology  2012;36(3):201-207.
Background/Aims
Although annual influenza vaccination is recommended for kidney transplant recipients, efficacy as reflected by serum antibody titers has not been well studied beyond 1 month in kidney transplant recipients.
Methods
We performed a single center prospective cohort study of 51 kidney transplant recipients and 102 healthy controls receiving the 2006–2007 influenza vaccine. Anti-hemagluttinin antibody titers to A/H1N1, A/H3N2, and B were measured prior and 1 month after vaccination, and again at the end of influenza season. The primary outcome was the proportion of participants maintaining seroprotection (antibody titer ≥ 1:32) for the duration of influenza season after influenza vaccination.
Results
Median follow up time was 175 and 155 days in the transplant and control groups, respectively. For types A/H1N1 and B, a similar high proportion of the transplant and control groups (88.5% and 81.6% vs 83.7% and 74.2% for A/H1N1 and B, respectively) maintained seroprotection. For type A/H3N2, significantly less of the transplant group (66.7%) versus the control group (90%) maintained a protective influenza vaccine response (odds ratio 0.21, 95% CI 0.07–0.64). This difference disappeared in adjusted analyses. Actual geometric mean titers decreased significantly within both groups (P < 0.001) but this did not differ between groups.
Conclusions
Once they have developed protective vaccine-induced antibody responses to influenza vaccine, kidney transplant recipients are able to maintain adequate protective levels of antibody compared with healthy controls.
doi:10.1159/000341653
PMCID: PMC3482977  PMID: 22906930
transplant; influenza; vaccine; immunosuppression
6.  Kidney Measures with Diabetes and Hypertension on Cardiovascular Disease: the Atherosclerosis Risk in Communities Study 
American journal of nephrology  2015;41(0):409-417.
Background
Whether the association of chronic kidney disease (CKD) with cardiovascular risk differs by diabetes and hypertension status remains unanswered.
Methods
We investigated 11,050 participants from the ARIC Study (fourth examination [1996–1998]) with follow-up for cardiovascular outcomes (coronary disease, heart failure, and stroke) through 2009. Using Cox regression models, we quantified cardiovascular risk associated with estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR) in individuals with and without diabetes and/or hypertension and assessed their interactions.
Results
Individuals with diabetes and hypertension generally had higher cardiovascular risk relative to those without at all levels of eGFR and ACR. Cardiovascular risk increased with lower eGFR and higher ACR regardless of diabetes and hypertension status (e.g., adjusted hazard ratio [HR] for eGFR 30–44 vs. 90–104 mL/min/1.73m2, 2.32 [95% CI, 1.66–3.26] in non-diabetics vs. 1.83 [1.25–2.67] in diabetics and 2.45 [2.20–5.01] in non-hypertensives vs. 1.51 [1.27–1.81] in hypertensives and corresponding adjusted HR for ACR 30–299 vs. <10 mg/g, 1.70 [1.45–2.00] vs. 1.34 [1.10–1.64] and 1.42 [1.10–1.85] vs. 1.57 [1.36–1.81], respectively). Only the ACR-diabetes interaction reached significance, with a shallower relative risk gradient among diabetes than non-diabetes (p=0.02). Analysis of individual cardiovascular outcomes showed similar results.
Conclusion
Although individuals with diabetes and hypertension generally had higher cardiovascular risk relative to those without these complications, both low eGFR and high ACR were associated with cardiovascular disease regardless of the presence or absence of diabetes and hypertension status. These findings reinforce the importance of CKD in cardiovascular outcomes.
doi:10.1159/000433450
PMCID: PMC4550225  PMID: 26139323
chronic kidney disease; diabetes; hypertension; cardiovascular disease
7.  Deletion of UNC5B in kidney epithelium exacerbates diabetic nephropathy in mice 
American journal of nephrology  2015;41(3):220-230.
Background
Guidance cue netrin-1 was shown to have protective effects in diabetic nephropathy. However, the role of its receptor UNC5B in diabetic kidney disease is unknown. Moreover, whether netrin-1 is protective against diabetic kidney disease in a genetic model of nephropathy and in the nephropathy prone DBA background is also unknown. The aim of this study is to determine the significance of UNC5B in tubular epithelial cells in chronic kidney disease due to diabetes and evaluate whether netrin-1 is also protective in a nephropathy prone mouse background.
Methods
Proximal tubular epithelium specific UNC5B knockout mice as well as heterozygous UNC5B knockout mice were used to determine the roles of UNC5B in nephropathy. Diabetes was induced in these tissue specific knockout, heterozygous and WT mice and albuminuria was then monitored.
Results
WT and heterozygous diabetic mice developed significant albuminuria at 8 weeks after induction of diabetes as compared to buffer treated control mice. However, albuminuria was significantly more pronounced in mice with proximal tubule specific deletion of UNC5B. Transgenic overexpression of netrin-1 in proximal tubules in the DBA background and administration of recombinant netrin-1 to Ins2Akita mice also significantly reduced diabetes induced albuminuria and suppressed glomerular and interstitial lesions.
Conclusion
Our data suggest that netrin-1 signaling in proximal tubular epithelium may play a critical role in the protection of kidney against diabetic kidney disease.
doi:10.1159/000381428
PMCID: PMC4441848  PMID: 25896231
UNC5B; Diabetic Nephropathy; Netrin-1
8.  RENAL C3 COMPLEMENT COMPONENT: FEED FORWARD TO DIABETIC KIDNEY DISEASE 
American journal of nephrology  2015;41(1):48-56.
Background
Diabetic nephropathy is the main cause of end-stage renal disease and has reached epidemic proportions.
Methods
Comprehensive genomic profiling (RNA Seq) was employed in the ZS (F1 hybrids of Zucker and spontaneously hypertensive heart failure) model of diabetic nephropathy. Controls were lean littermates.
Results
Diabetic nephropathy in obese, diabetic ZS was accelerated by a single episode of renal ischemia (DI). This rapid renal decline was accompanied by activation of the renal complement system in DI, and to a lesser extent in sham operated diabetic rats (DS). In DI there were significant increases in renal mRNA encoding C3, C4, C5, C6, C8 and C9 over sham operated lean normal controls (LS). Moreover, mRNAs encoding the receptors for the anaphylatoxins C3a and C5a were also significantly increased in DI compared to LS. The classic complement pathway was activated in diabetic kidneys with significant increases of C1qa, C1qb, and C1qc mRNAs in DI over LS. In addition, critical regulators of complement activation were significantly attenuated in DI and DS. These included mRNAs encoding CD55, decay accelerating factor, and CD59, which inhibits the membrane attack complex. C3, C4 and C9 proteins were demonstrated in renal tubules and glomeruli. The complement RNAseq data were incorporated into a gene network showing interactions among C3 generating renal tubular cells and other immune competent migratory cells.
Conclusions
We conclude that local activation of the complement system mediates renal injury in diabetic nephropathy.
doi:10.1159/000371426
PMCID: PMC4351877  PMID: 25662584
complement; diabetic nephropathies; ischemia; kidney failure; chronic
9.  THE RELATIONSHIP BETWEEN ULTRAVIOLET LIGHT EXPOSURE AND MORTALITY IN DIALYSIS PATIENTS 
American journal of nephrology  2014;40(3):224-232.
Background
Emerging data suggest that reduced exposure to ultraviolet (UV) radiation is associated with increased mortality in the general population. To date, there has not been examination of the association between UV exposure and mortality in dialysis patients.
Methods
We examined the association between UV index, a proxy of UV exposure, and all-cause mortality among 47,286 US dialysis patients (entry period 2001–2006, with follow-up through 2009) from a large national dialysis organization using multivariable Cox regression. The UV index was ascertained by linkage of individual patients’ residential zip codes to National Oceanic and Atmospheric Administration data, and was categorized as low (0–<3), moderate (3–<5), moderate-high (5–<6), high (6–<7), and very-high (≥7). In secondary analyses, we examined the UV index—mortality association within subgroups of age (<65 vs. ≥ 65 years old), sex, and race (white vs. non-white).
Results
The study population’s mean±SD age was 60±16 years old and included 46% women and 56% diabetics. Compared to patients residing in moderate-high UV index regions, those residing in high and very-high UV index regions had lower mortality risk: adjusted HRs 0.84 (95% CI) 0.81–0.88 and 0.83 (95% CI) 0.75–0.91, respectively. A similar inverse association between UV index and mortality was observed across all subgroups, although there was more pronounced reduction in mortality among whites vs. non-whites.
Conclusion
These data suggest that dialysis patients residing in higher UV index regions have lower all-cause mortality compared to those living in moderate-high UV regions. Further studies are needed to determine mechanisms underlying the UV index—mortality association.
doi:10.1159/000367903
PMCID: PMC4283141  PMID: 25322752
Dialysis; environment; mortality; ultraviolet radiation; vitamin D
10.  Association of U.S. Dialysis Facility Neighborhood Characteristics with Facility-Level Kidney Transplantation 
American journal of nephrology  2014;40(2):164-173.
Background
Improving access to optimal healthcare may depend on attributes of neighborhoods where patients receive healthcare services. We investigated whether characteristics of dialysis facility neighborhoods—where most patients with end-stage renal disease are treated—were associated with facility-level kidney transplantation.
Methods
We examined the association between census tract (neighborhood)-level sociodemographic factors and facility-level kidney transplantation rate in 3,983 U.S. dialysis facilities with reported kidney transplantation rates. Number of kidney transplants and total person-years contributed at the facility level in 2007-2010 were obtained from the Dialysis Facility Report and linked to census tract data on sociodemographic characteristics from the American Community Survey 2006-2010 by dialysis facility location. We used multivariable Poisson models with generalized estimating equations to estimate associations between neighborhood characteristics and transplant incidence.
Results
U.S. dialysis facilities were located in neighborhoods with substantially greater proportions of black and poor residents, relative to the national average. Most facility neighborhood characteristics were associated with transplant, with incidence rate ratios (95% CI) for standardized increments (in percentage) of neighborhood exposures of: living in poverty, 0.88 (0.84-0.92), black race, 0.83 (0.78-0.89); high school graduates, 1.22 (1.17-1.26); and unemployed, 0.90 (0.85-0.95).
Conclusion
Dialysis facility neighborhood characteristics may be modestly associated with facility rates of kidney transplantation. The success of dialysis facility interventions to improve access to kidney transplantation may partially depend on reducing neighborhood-level barriers.
doi:10.1159/000365596
PMCID: PMC4175288  PMID: 25196018
Neighborhood; Dialysis Facility; Kidney Transplantation; Socioeconomic Status
11.  Prevalence of Cardiovascular Events in Patients with Autosomal Dominant Polycystic Kidney Disease 
American journal of nephrology  2012;36(4):362-370.
Background
This study evaluates the prevalence of cardiovascular events in autosomal dominant polycystic kidney disease (ADPKD) patients.
Methods
We distributed surveys to 1439 subjects from our ADPKD research database. 426 subjects with ADPKD completed and returned surveys. Seven of 426 surveys returned were children and were excluded from the study.
Results
ADPKD patients responding were female (63.2%), non-Hispanic (88.1%) and white (93.6%). The mean age of total group was 53.2 ± 13.7 years. 82.8% had a family history of ADPKD and 32.5% had reached end-stage renal disease (ESRD). With respect to cardiovascular risk factors 86.6% were hypertensive with a mean age at diagnosis of 36.9 ± 12.9 years and hypertension was significantly more prevalent in males. In addition, 19.6% of subjects were obese, 20.8% were smokers, 8.7% had diabetes, 45.7% had high cholesterol and 17.8% were sedentary. The most prevalent self reported cardiovascular events were arrhythmias (25.9%), evidence of peripheral vascular disease (16.5%), heart valve problems (14.4%), cardiac enlargement (9.5%), stroke or cerebral bleeding (7.5%), myocardial infarction (6%) and brain aneurysm (5.0%). The most commonly used antihypertensive medications were renin-angiotensin inhibitors used by 75% of ADPKD patients. Older ADPKD patients and those at ESRD had a significantly higher incidence of cardiovascular events.
Conclusion
These findings support the high prevalence of cardiovascular risk factors and events in ADPKD patients and thus increasing risk for mortality. Due to the prevalence of cardiovascular risk factors in the ADPKD population, early diagnosis and clinical intervention are recommended.
doi:10.1159/000343281
PMCID: PMC4527158  PMID: 23038404
Autosomal dominant polycystic kidney disease; cardiovascular events; risk factor; morbidity; mortality
12.  Urinary sodium is a potent correlate of proteinuria: Lessons from the CRIC Study 
American journal of nephrology  2012;36(5):397-404.
Background
While higher blood pressure is known to increase proteinuria, whether increased dietary sodium as estimated from 24-hour urinary excretion correlates with increased proteinuria in patients with chronic kidney disease (CKD) is not well studied.
Methods
We measured 24-hour urine sodium, potassium, and protein excretion in 3,680 participants in the Chronic Renal Insufficiency Cohort (CRIC) study, to determine the relationship between urinary sodium and potassium and urinary protein excretion in patients with CKD. We stratified our data based on the presence or absence of diabetes given the absence of any data on this relationship, and evidence that diabetics had greater urinary protein excretion at nearly every level of urinary sodium excretion. Multiple linear regressions were used with a stepwise inclusion of covariates such as systolic blood pressure (SBP), demographics, hemoglobin A1C, and type of antihypertensive medications to evaluate the relationship between urinary electrolyte excretion and proteinuria.
Results
Our data demonstrated that urinary sodium (+1SD above the mean), as a univariate variable, explained 12% of the variation in proteinuria (β=0.29, p<.0001) with rising urinary sodium excretion associated with increasing proteinuria. The significance of that relationship was only partially attenuated with adjustment for demographic and clinical factors and the addition of 24-hour urinary potassium to the model (β=0.13, R2=0.35, p<.0001).
Conclusions
An understanding of the relationship between these clinical factors and dietary sodium may allow a more tailored approach for dietary salt restriction in patients with CKD.
doi:10.1159/000342966
PMCID: PMC4448958  PMID: 23076013
proteinuria; sodium; potassium; blood pressure
13.  Effect of Food Insecurity on Chronic Kidney Disease in Lower Income Americans 
American journal of nephrology  2014;39(1):27-35.
Background
The relation of food insecurity (inability to acquire nutritionally adequate and safe foods) and chronic kidney disease (CKD) is unknown. We examined whether food insecurity is associated with prevalent CKD among lower income individuals in both the general U.S. adult population and an urban population.
Methods
We conducted cross-sectional analyses of lower income participants of the National Health and Nutrition Examination Survey (NHANES) 2003–2008 (n=9,126); and the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study (n=1,239). Food insecurity was defined based on questionnaires and CKD was defined by reduced estimated glomerular filtration rate or albuminuria; adjustment was performed with multivariable logistic regression.
Results
In NHANES, the age-adjusted prevalence of CKD was 20.3%, 17.6% and 15.7% for the high, marginal and no food insecurity groups, respectively. Analyses adjusting for sociodemographics and smoking status revealed high food insecurity to be associated with greater odds of CKD only among participants with either diabetes [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.14–2.45 comparing high to no food insecurity group] or hypertension (OR 1.37, 95% CI 1.03–1.82). In HANDLS, the age-adjusted CKD prevalence was 5.9% and 4.6% for those with and without food insecurity, respectively (P=0.33). Food insecurity was associated with a trend towards greater odds of CKD (OR 1.46, 95% CI 0.98–2.18) with no evidence of effect modification across diabetes, hypertension or obesity subgroups.
Conclusion
Food insecurity may contribute to disparities in kidney disease, especially among persons with diabetes or hypertension, and is worthy of further study.
doi:10.1159/000357595
PMCID: PMC3952065  PMID: 24434743
renal; socioeconomic status; disparity; nutrition
14.  Prevalence and Correlates of Fatigue in CKD and ESRD: Are Sleep Disorders a Key to Understanding Fatigue? 
American journal of nephrology  2013;38(6):489-495.
Background
Fatigue is an important symptom to patients with advanced CKD. The aim of this study is to examine the prevalence and severity of fatigue among non-dialysis dependent CKD and ESRD patients; examine association of fatigue with subjective and objective sleep quality; identify other modifiable factors associated with fatigue.
Methods
Cross-sectional survey of 87 non-dialysis dependent CKD (eGFR ≤45 ml/min/1.73 m2) and 86 ESRD patients was done using Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) and SF-36 vitality scale. Higher FACIT-F score denoted less fatigue. Objective sleep was assessed using in-home polysomnography. Predictors of fatigue were determined using linear regression model.
Results
Mean FACIT-F score among all participants was 34.5±11.0. Mean scores were similar among CKD and ESRD groups (34.25±11.28 versus 34.73±10.86; p=0.73). On univariate analyses, patients with higher levels of fatigue were more likely to have cardiovascular disease, benzodiazepine use, depressive symptoms, slightly lower hemoglobin and serum albumin levels. There was no significant association between severity of sleep apnea and level of fatigue (Apnea Hypopnea Index 20.1±27.6 versus 20.3±22.0; p=0.69). Presence of cardiovascular disease, low serum albumin, depressive symptoms, poor subjective sleep quality, excessive daytime sleepiness and restless legs syndrome (RLS) were independently associated with greater fatigue in multivariable regression models. The FACIT-F score correlated closely with the SF-36 vitality score (r =0.81, p<0.0001).
Conclusions
Patients with advanced CKD and ESRD experience profound fatigue. Depressive symptoms, RLS, excessive daytime sleepiness, and low albumin levels may provide targets for interventions to improve fatigue in patients with advanced CKD.
doi:10.1159/000356939
PMCID: PMC3925636  PMID: 24335380
End stage renal disease (ESRD); fatigue; sleep; chronic kidney disease; FACIT-F scale
15.  The role of p66shc in renal toxicity of oleic acid 
American journal of nephrology  2013;38(3):10.1159/000354357.
Background/Aims
Adult and childhood obesity is an independent risk factor in development of chronic kidney disease (CKD) and its progression to end-stage kidney disease (ESRD). Pathologic consequences of obesity include non-esterified fatty acid (NEFA)-induced oxidative stress and consequent injury. Since the serine36 phosphorylated p66shc is a newly recognized mediator of oxidative stress and kidney injury, we studied its role in oleic acid (OA)-induced production of reactive oxygen species (ROS), mitochondrial depolarization and injury in cultured renal proximal tubule cells (RPTCs).
Methods
RPTCs were used and treated with oleic acid (OA): ROS production, mitochondrial depolarization as well as injury were determined. Transcriptional effects of OA on the p66shc gene were determined in a reporter luciferase assay. The role of p66shc in adverse effects of OA was determined using knockdown, p66shc serine36 phosphorylation and cytochrome c-binding deficient cells.
Results
We found that OA increased ROS production via the mitochondria –and in less extent via the NADPH oxidase- resulting in ROS-dependent mitochondrial depolarization and consequent injury. Interestingly, OA also stimulated the promoter of p66shc. Hence, knockdown of p66shc, impairment its Ser36 phosphorylation (mutation of Ser36 residue to alanine) or cytochrome c binding (W134F mutation) significantly attenuated OA-dependent lipotoxicity.
Conclusion
These results offer a novel mechanism by which obesity may lead to renal tubular injury and consequently development of CKD. Manipulation of this pathway may offer therapeutic means to ameliorate obesity-dependent renal lipotoxicity.
doi:10.1159/000354357
PMCID: PMC3818798  PMID: 23988748
lipotoxicity; renal; p66shc; ROS; mitochondria; depolarization; injury
16.  Changes in Biomarkers Associated With Living Kidney Donation 
American journal of nephrology  2013;38(3):10.1159/000354312.
Living donor kidneys have been associated with better graft and overall survival in kidney transplant recipients. Although living kidney donation is generally considered safe in carefully selected living donors, concerns of possible adverse effects related to kidney donation remain, especially in younger and high risk donors. In this study, we examined the changes in a panel of traditional and novel serum biomarkers linked with cardiovascular conditions in a cohort of 34 healthy living kidney donors with a mean age(SD) of 40±10 years and estimated pre-donation GFR of 86±10 ml/min/1.73m2. At 6 months post donation, there were no significant changes in the clinical parameters including body mass index (BMI) and blood pressure despite a significant decline in the mean estimated GFR to 60 ml/min/1.73m2. Among the panel of markers, the levels of symmetric dimethylarginine (SDMA) and fibroblast growth factor 23(FGF-23) increased significantly compared to baseline, suggesting that living kidney donation may result in changes in biomarkers that are associated with cardiovascular risk in other cohorts.
doi:10.1159/000354312
PMCID: PMC3838917  PMID: 23988698
biomarkers; cardiovascular; transplantation; risk factors
17.  Prevalence of 25-OH Vitamin D Deficiency in a Population of Hemodialysis Patients and Efficacy of an Oral Ergocalciferol Supplementation Regimen 
American journal of nephrology  2013;37(6):568-574.
Background/Aims
Optimal dosing regimens for 25-OH vitamin D (VitD) deficiency are unknown in hemodialysis (HD) patients. Our aim was to evaluate the efficacy of prescribing ergocalciferol supplementation based on KDOQI guidelines for chronic kidney disease (CKD) stages III–IV in HD patients.
Methods
We conducted a retrospective study of 96 urban, predominately African-American HD patients at a single-center dialysis unit with VitD insufficiency or deficiency treated with ergocalciferol. Patients were classified as either compliant or non-compliant with supplementation as determined by review of pharmacy records. The primary outcome was VitD levels 6 months after initiation of treatment and secondary outcomes were VitD levels at 11 months, bone/mineral and anemia parameters.
Results
The population was predominately African-American (69%) and Hispanic (28%). There were 61 individuals in the compliant group and 35 individuals in the non-compliant group. The compliant group was older but otherwise similar in demographics and co-morbid conditions to the non-compliant group. After 6 months of treatment, the compliant group had a significant increase in VitD level (14.7 ± 6.0 to 28.7 ± 10.0 ng/ml, p < 0.0001) compared to the non-compliant group (14.7 ± 5.5 to 14.8 ± 7.1 ng/ml, p = 0.95). There were no differences in the incidence of hypercalcemia between the two groups. Except for a decrease in phosphorus in the compliant group (5.6 ± 1.6 to 4.9 ± 1.7 mg/dl, p = 0.004), there were no significant difference in bone/mineral or anemia parameters including dosing of darbepoetin.
Conclusion
An ergocalciferol-prescribing strategy using the KDOQI guidelines for stage III–IV kidney disease in HD patients with VitD deficiency or insufficiency is inadequate to achieve repletion or maintenance of normal VitD levels.
doi:10.1159/000351185
PMCID: PMC4109679  PMID: 23735861
Vitamin D deficiency; End-stage renal disease; Hemodialysis
18.  Iron Sucrose Impairs Phagocytic Function and Promotes Apoptosis in Polymorphonuclear Leukocytes 
American journal of nephrology  2012;36(1):50-57.
Background
With the recent implementation of bundling reimbursement policy the use of intravenous (IV) iron preparations for the management of anemia in the ESRD population has dramatically increased. Iron overload increases the risk of infections in individuals with or without kidney disease. IV iron administration in ESRD patients impairs bacteriocidal capacity of PMNs against Escherichia Coli. These preparations consist of an elemental iron core and a carbohydrate shell. In addition to the iron core the carbohydrate shell may affect PMNs. We therefore examined the effect of iron sucrose, a commonly used preparation, on phagocytic capacity of PMNs from a group of normal individuals against Gram positive (Staphylococcus Aureus) and Gram negative (E. Coli) bacteria.
Methods
Iron sucrose was added to heparinized blood samples at pharmacologically-relevant concentrations and incubated for 4 and 24 hours at 37° C to simulate in vivo condition. Blood samples mixed with equal volume of saline solution served as controls. To isolate the effects of the carbohydrate shell, blood samples were co-treated with the iron chelator, desferrioxamine.
Results
Iron sucrose caused significant PMN apoptosis and dose-dependent suppression of phagocytic function against both Gram positive and negative bacteria. These abnormalities were prevented by desferrioxamine which precluded contribution of the carbohydrate shell to the PMN dysfunction.
Conclusions
At pharmacologically-relevant concentrations iron sucrose promotes apoptosis and inhibits phagocytic activities of PMNs. The deleterious effect of iron sucrose is mediated by its elemental iron core, not its carbohydrate shell, and as such may be shared by other IV iron preparations.
doi:10.1159/000339285
PMCID: PMC3986045  PMID: 22722756
Iron; Infection; Inflammation; Immune deficiency; Anemia; End-stage renal disease; Dialysis
19.  Using Hemoglobin A1c to Derive Mean Blood Glucose in Peritoneal Dialysis Patients 
American journal of nephrology  2013;37(5):10.1159/000349929.
Background
Although hemoglobin A1c (HbA1c) has been widely used as a clinical assessment tool for outcome analyses related to glycemic control, the relationship between HbA1c and average blood glucose (BG) specific to peritoneal dialysis (PD) patients with diabetes has not been characterized. We sought to develop HbA1c-BG equation models for PD patients.
Methods
We examined associations between HbA1c and random serum BG values over time in a contemporary 5-year (2001–2006) cohort of DaVita PD patients with diabetes. We identified 850 patients (mean age 58±13 years old and 56% male) with 4,566 paired measurements of HbA1c and BG. The bootstrapping method was used to estimate average BG and corresponding HbA1c.
Results
Linear regression analyses yielded the following HbA1c-BG equations: (1) BG (mg/dL)=24.1 + 28.6 × HbA1c – 12.2 × Albumin (R2adj=0.454), (2) BG = 55.3+ 28.8 × HbA1c-10.2 × Albumin −3.3 × Hemoglobin (R2adj=0.457), (3) and BG =69.5 +28.7 × HbA1c- 10.1 × Albumin- 3.7 × Hemoglobin- 0.1 × Age+ Race/Ethnicity (−10.1 African-Americans, −5.4 other race/ethnicities; R2adj=0.457). All models showed greater explanatory power of BG variation than previously established HbA1c-BG equation models defined within non-PD cohorts (R2adj=0.446 for both the DCCT and the ADAG equations).
Conclusions
The association between HbA1c and BG in PD patients is different than that of patients with normal kidney function. Our analysis suggests that equations incorporating serum albumin and/or hemoglobin values better estimate the HbA1c-BG relationship in PD patients compared to equations using HbA1c alone.
doi:10.1159/000349929
PMCID: PMC3844668  PMID: 23594745
Hemoglobin A1c; blood glucose; equation model; glycemic control; albumin; hemoglobin; peritoneal dialysis; race
20.  Role of urea in intestinal barrier dysfunction and disruption of epithelial tight junction in CKD 
Background
Chronic kidney disease (CKD) impairs intestinal barrier function which leads to endotoxemia and systemic inflammation. We have found depletion of intestinal epithelial tight junction (TJ) proteins in animals with CKD. We further showed that addition of ESRD patients' plasma to the culture medium provokes marked drop in transepithelial electrical resistance (TER) and depletion of TJ proteins in cultured human enterocytes. These effects were less severe with post- than pre-hemodialysis plasma suggesting the role of dialyzable agent(s). This study tested the hypothesis that intestinal barrier dysfunction in uremia may be due to diffusion of urea into the gut and its conversion to ammonia by microbial urease.
Methods
Human enterocytes (T84 cells) were seeded on Transwell plates and utilized when TER exceeded 1,000 Ω.cm2 to ensure full polarization and TJ formation. Confluent cells were then incubated for 24 hr in media containing zero, 42, or 74 mg/dl urea or urea plus urease to simulate presence of microbial flora.
Results
At clinically-relevant concentrations, urea caused a concentration-dependent fall in TER and the key TJ protein; cluadin-1, occludin, and ZO1. The effects of urea were dramatically amplified by urease causing cells detachment, dissipation of TER, and massive loss of TJ proteins.
Conclusions
uremia-induced disruption of intestinal TJ and barrier function is, in part, mediated by urea which is generally considered to be a nontoxic retained metabolite. These findings reveal a novel mechanism for salutary effect of urea-lowering strategies e.g. low protein diet and longer and more frequent dialysis regimens in advanced CKD.
doi:10.1159/000345969
PMCID: PMC3686571  PMID: 23258127
Endotoxin; Inflammation; Gastrointestinal pathology; End-stage renal disease; uremia; cardiovascular disease
21.  Association between kidney function and telomere length: the Heart and Soul Study 
American journal of nephrology  2012;36(5):405-411.
Background
Telomere attrition is a novel risk factor for cardiovascular disease. Studies of telomere length in relation to kidney function are limited. We explored the association of kidney function with telomere length and telomere shortening.
Methods
The Heart and Soul study is a longitudinal study of patients with stable coronary heart disease (CHD). Measures of baseline kidney function included: serum creatinine, creatinine-derived estimated glomerular filtration rate (eGFRCKD-EPI), 24-hour urine measured creatinine clearance, cystatin C, cystatin C-derived estimated glomerular filtration rate (eGFRcys) and urine albumin to creatinine ratio. Telomere length was measured from peripheral blood leukocytes at baseline (N=954) and 5 years later (N=608). Linear regression models were used to test the association of kidney function with i) baseline telomere length and ii) change in telomere length over 5 years.
Results
At baseline, mean eGFRCKD-EPI was 72.6 (± 21.5) ml/min/1.73 m2, eGFRcys was 71.0 (± 23.1) ml/min/1.73 m2 and ACR was 8.6 (±12.3) mg/gm. Only lower baseline eGFRCKD-EPI was associated with shorter baseline telomere length (9.1 [95% CI 1.2–16.9] fewer base pairs for every 5 ml/min/1.73 m2 lower eGFRCKD-EPI). Lower baseline eGFRCKD-EPI (and all other measures of kidney function) predicted more rapid telomere shortening (10.8 [95% CI 4.3–17.3] decrease in base pairs over 5 years for every 5 ml/min/1.73 m2 lower eGFRCKD-EPI). After adjustment for age, these associations were no longer statistically significant.
Conclusions
In patients with CHD, reduced kidney function is associated with i) shorter baseline telomere length and ii) more rapid telomere shortening over 5 years, however these associations are entirely explained by older age.
doi:10.1159/000343495
PMCID: PMC3552638  PMID: 23108000
kidney; CKD; telomere
22.  Carotid Plaque, Carotid Intima-Media Thickness, and Coronary Calcification Equally Discriminate Prevalent Cardiovascular Disease in Kidney Disease 
American journal of nephrology  2012;36(4):342-347.
Background
Despite the significant morbidity and mortality attributable to cardiovascular disease (CVD), risk stratification remains an important challenge in the chronic kidney disease(CKD) population. We examined the discriminative ability of non-invasive measures of atherosclerosis, including carotid intima-media thickness(cIMT), carotid plaque, coronary artery calcification(CAC) and ascending and descending thoracic aorta calcification(TCAC), and Framingham Risk Score (FRS) to predict self-reported prevalent CVD.
Methods and Results
Participants were enrolled in the cIMT ancillary study of the Chronic Renal Insufficiency Cohort(CRIC) Study and also had all of the above measures within an 18 month period. CVD was present in 21% of study participants. C-statistics were used to ascertain the discriminatory power of each measure of atherosclerosis. The study population (n=220) was 64% male; 51% black and 45% white. The proportion of individuals with estimated glomerular filtration rate ≥60, 45–59, 30–44, and <30ml/min/1.73m2 was 21%, 41%, 28%, and 11%, respectively. In multivariable analyses adjusting for demographic factors, we failed to find a difference between CAC, carotid plaque, and cIMT as predictors of self-reported prevalent CVD (c-statistic 0.70, 95% confidence interval [CI]: 0.62–0.78; c-statistic 0.68, 95% CI: 0.60–0.75, and c-statistic 0.64, CI: 0.56–0.72, respectively). CAC was statistically better than FRS. FRS was the weakest discriminator of self-reported prevalent CVD (c-statistic 0.58).
Conclusions
There was a significant burden of atherosclerosis among individuals with CKD, ascertained by several different imaging modalities. We were unable to find a difference in the ability of CAC, carotid plaque, and cIMT to predict self-reported prevalent CVD.
doi:10.1159/000342794
PMCID: PMC3538165  PMID: 23107930
carotid intima media thickness; coronary artery calcification; kidney; plaque
23.  Risk factor, age and sex differences in chronic kidney disease prevalence in a diabetic cohort: The Pathways Study 
American journal of nephrology  2012;36(3):245-251.
Background/Aims
Women with diabetes experience a disproportionately greater burden of diabetic kidney disease (DKD) risk factors compared to men, however sex-specific differences in DKD are not well defined. The effect of age on sex differences in DKD is unknown.
Methods
We performed a cross-sectional analysis of the prevalence of DKD (eGFR <60 ml/min/1.73m2 or microalbuminuria), advanced DKD (eGFR <30 ml/min/1.73 m2), and common DKD risk factors in the Pathways Study (N = 4,839), a prospective cohort study of diabetic patients from a managed care setting. Subjects were stratified by age <60 and ≥60 years to examine for differences by age. Logistic regression models examined the association between sex and prevalence of DKD and risk factors.
Results
Women of all ages had 28% decreased odds of DKD (OR 0.72, 95% CI 0.62–0.83); however, they had a greater prevalence of advanced DKD (OR 1.67, 95% CI 1.05–2.64), dyslipidemia (OR 1.42 95% CI 1.16–1.74), and obesity (OR 1.87, 95% CI 1.60–2.20) compared to men. Women had similar odds of hypertension and poor glycemic control as men. Women ≥60 years had increased odds of advanced DKD, hypertension, dyslipidemia, and obesity compared to similarly aged men. Women <60 years had increased odds of obesity compared to their male counterparts.
Conclusion
Women with diabetes had an increased prevalence of advanced DKD and common DKD risk factors compared to men and these disparities were most prominent amongst the elderly.
doi:10.1159/000342210
PMCID: PMC3510352  PMID: 22964976
sex difference; gender difference; diabetic kidney disease
24.  Polymorphisms in the Nonmuscle Myosin Heavy Chain 9 Gene (MYH9) Are Associated with Albuminuria in Hypertensive African Americans: The HyperGEN Study 
American Journal of Nephrology  2009;29(6):626-632.
Background
MYH9 is a podocyte-expressed gene encoding nonmuscle myosin IIA that is associated with idiopathic and human immunodeficiency virus-associated focal segmental glomerulosclerosis (FSGS) and hypertensive end-stage renal disease in African Americans.
Methods
Four single nucleotide polymorphisms comprising the major MYH9 E1 risk haplotype were tested for association with estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (ACR) in 2,903 HyperGEN participants (1,458 African Americans (AA) in 895 families and 1,445 European Americans (EA) in 859 families) to determine the role of MYH9 in subclinical nephropathy. Association analyses employed general linear models in unrelated probands and generalized estimating equations in families. Adjustment was performed for age, sex, diabetes, BMI, medications, and mean arterial pressure separately in each race.
Results
Mean (SD) eGFR and ACR were 74.3 (16.0) ml/min/1.73 m2 and 20.3 (119.9) mg/g in EA, and 88.6 (20.9) ml/min/1.73 m2 and 76.8 (394.5) mg/g in AA (both p < 0.0001 across ethnicities). Urine ACR was associated with rs3752462 (p = 0.01) and rs4821481 (p = 0.05) in unrelated AA and with rs4821481 (p = 0.03), rs2032487 (p = 0.04) and the E1 3224 haplotype (p = 0.013) in AA families. Single nucleotide polymorphisms and the haplotype were not associated with ACR in EA or with eGFR in either ethnic group.
Conclusions
MYH9 variants are associated with albuminuria in hypertensive AA. The strength of the association was weaker than that in FSGS and hypertensive end-stage renal disease. MYH9 risk variants appear to be associated with primary FSGS with secondary hypertension, although nephrosclerosis may develop in response to hypertension in subjects homozygous for the MYH9 E1 risk haplotype.
doi:10.1159/000194791
PMCID: PMC2749685  PMID: 19153477
African Americans; Albuminuria; Chronic kidney disease; Essential hypertension; HyperGEN study; MYH9 gene
25.  Preservation of blood pressure stability with hypertonic mannitol during hemodialysis initiation 
American journal of nephrology  2012;36(2):168-174.
Background
Intra-dialytic hypotensive events are common among hemodialysis patients and are associated with a variety of patient and procedure related factors, including intra-dialytic decline in plasma osmolality. Prior studies and practice have suggested that administration of osmotically active drugs may ameliorate blood pressure decline during chronic hemodialysis.
Methods
Clinical and treatment data was collected for 102 consecutive patients requiring initiation of renal replacement therapy in 2 major teaching hospitals. Routine administration of mannitol differed according to institutional protocols, allowing its examination as the primary exposure of interest. Generalized linear models were fit to estimate associations of mannitol use during dialysis initiation with intra-dialytic blood pressure, as assessed by: 1) intra-dialytic blood pressure decline; 2) nadir intra-dialytic blood pressure; 3) absolute systolic blood pressure <90mmHg or decline >20mmHg.
Results
Mean age was 62 years (±16), 70% were male and 44% were diabetic. Mean pre-dialysis and nadir systolic blood pressure were 142mmHg (±29) and 121mmHg (±26) respectively. Mannitol administration was associated with less decline in intra-dialytic blood pressure, a higher nadir blood pressure and fewer hypotensive events requiring intervention. No effect modification was evident according to diabetes or acuity of kidney disease (chronic vs acute).
Conclusions
Mannitol administration appears to preserve hemodynamic stability during hemodialysis initiation. Randomized controlled trials are needed to confirm these findings and identify optimal management strategies to prevent intra-dialytic hypotension.
doi:10.1159/000341273
PMCID: PMC3779621  PMID: 22846598
hemodialysis; intra-dialytic hypotension; mannitol; osmolality

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