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26.  Statin Use and Calcific Uremic Arteriolopathy: A Matched Case-Control Study 
American journal of nephrology  2013;37(4):325-332.
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.
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.
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).
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.
PMCID: PMC4110510  PMID: 23548843
Calcific uremic arteriolopathy; Calciphylaxis; Case control; Statin; Vitamin D
27.  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.
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.
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.
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.
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.
PMCID: PMC4109679  PMID: 23735861
Vitamin D deficiency; End-stage renal disease; Hemodialysis
American journal of nephrology  2013;38(1):10.1159/000351764.
Little is known about risk factors for sudden cardiac death in hemodialysis patients during the high-risk first year of dialysis. We therefore undertook to identify such risk factors in a nationally representative cohort and were able to include baseline levels of blood fatty acids, some of which influence arrhythmogenicity and sudden cardiac death risk.
The study cohort included 100 patients who died of sudden cardiac during the first year of hemodialysis and 300 frequency-matched controls. Using the elastic net statistical method, numerous demographic and clinical characteristics were included with baseline total serum levels for eleven major fatty acids (Model 1) and with serum phospholipid fractions of these same fatty acids (Model 2). Final models included only covariates that had a non-zero coefficient.
In Model 1, serum albumin (odds ratio (95% CI): 0.55(0.33,0.93), P=0.03) and total serum long chain n-3 docosapentaenoic acid (0.70(0.51,0.97), P=0.03) were inversely associated with odds of sudden cardiac death, while the total serum saturated fatty acid level had a direct association (1.01(1.00,1.02), P=0.03). In Model 2, serum albumin and docosapentaenoic acid remained inversely associated with sudden cardiac death in a similar manner as in model 1. Pulse pressure also had an inverse association (0.96(0.93,1.00), P<0.05).
Several factors, including blood content of docosapentaenoic acid and saturated fatty acids, were associated with odds of sudden cardiac death during year one of hemodialysis. These results raise the possibility that dietary modification may reduce sudden death risk.
PMCID: PMC3856432  PMID: 23816975
omega-3; fatty acids; sudden cardiac death; hemodialysis; incident; risk factors; nutrition; cardiovascular
29.  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.
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.
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.
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.
PMCID: PMC3777856  PMID: 23689670
Epithelial tight junction; Endotoxin; activated charcoal; ESRD; uremia
30.  Association between Dietary Sodium and Potassium Intake with Chronic Kidney Disease in U.S. Adults: A Cross-Sectional Study 
American journal of nephrology  2013;37(6):526-533.
Clinical guidelines recommend a diet low in sodium and high in potassium to reduce blood pressure and cardiovascular events. Little is known about the relationship between dietary sodium and potassium intake and chronic kidney disease (CKD).
13,917 participants from the National Health and Nutrition Examination Survey (2001–2006) were examined. Sodium and potassium intake were calculated from 24-hour recall and evaluated in quartiles. CKD was defined as eGFR <60 mL/min, or eGFR ≥ 60mL/min with albuminuria (>30mg/g creatinine).
The mean (SE) age and eGFR of participants was 45.0 ± 0.4 years and 88.0 ± 0.60 ml/min/1.73m2, respectively. 2333 (14.2%) had CKD: 1146 (7.3%) had an eGFR < 60 ml/min/1.73m2 and 1514 (8.4%) had an eGFR ≥ 60 ml/min/1.73 m2 and albuminuria. After adjustment for age, sex, race, body mass index, diabetes, hypertension, cardiovascular disease and congestive heart failure subjects in the highest quartile of sodium intake had a lower odds of CKD compared to subjects in the lowest quartile (adjusted OR 0.79, 95% CI, 0.66 to 0.96; p<0.016). Compared to the highest quartile, participants in the lowest quartile of potassium intake had a 44% increased odds of CKD (adjusted OR 1.44, 95% CI 1.16–1.79, p=0.0011).
Higher intake of sodium and potassium is associated with lower odds of CKD among US adults. These results should be corroborated through longitudinal studies and clinical trials designed specifically to examine the effects of dietary sodium and potassium intake on kidney disease and its progression.
PMCID: PMC3919025  PMID: 23689685
Chronic Kidney Disease; Dietary sodium intake; Dietary potassium intake
31.  Microalbuminuria in HIV Disease 
American journal of nephrology  2013;37(5):10.1159/000350384.
Microalbuminuria is a marker for early kidney disease and cardiovascular risk. The purposes of this study were to determine the prevalence of microalbuminuria in an HIV-infected clinic population, to test the predictive value of a single urine albumin-creatinine ratio (ACR) to identify persistent microalbuminuria and to examine covariates of microalbuminuria.
We conducted a prospective cohort study of HIV-infected subjects (n=182) without proteinuria (P/C ratio ≥0.5 g/g), elevated serum creatinine, diabetes, or chronic inflammatory conditions. Subjects completed three research visits within nine months. Microalbuminuria was defined as the geometric mean ACR of 25–355 mg/g for women and 17–250 mg/g for men.
The prevalence of microalbuminuria was 14%. The negative predictive value of a single urine ACR determination was 98%, whereas the positive predictive value was only 74%. Microalbuminuria was similar among Black (15%) and non-Black (14%) subjects (p=0.8). Subjects with microalbuminuria were more likely to have hypertension (p=0.02) and metabolic syndrome (p=0.03). While duration of HIV infection and the level of HIV viremia were similar between groups, those with microalbuminuria were more likely to have a CD4 count <200 cells/μL (p=0.0003). In a multivariate logistic regression analysis, the only significant independent predictors of microalbuminuria were low CD4 count (p=0.018) and current ritonavir exposure (p=0.04).
The prevalence of microalbuminuria in an HIV-infected clinic population was similar to earlier reports, and was associated with hypertension and impaired immune function. A single normal ACR determination effectively excludes microalbuminuria, whereas an elevated ACR requires confirmation.
PMCID: PMC3809894  PMID: 23615312
HIV infection; microalbuminuria; urinary albumin-creatinine ratio
32.  Iron Sucrose Impairs Phagocytic Function and Promotes Apoptosis in Polymorphonuclear Leukocytes 
American journal of nephrology  2012;36(1):50-57.
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.
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.
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.
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.
PMCID: PMC3986045  PMID: 22722756
Iron; Infection; Inflammation; Immune deficiency; Anemia; End-stage renal disease; Dialysis
33.  Using Hemoglobin A1c to Derive Mean Blood Glucose in Peritoneal Dialysis Patients 
American journal of nephrology  2013;37(5):10.1159/000349929.
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.
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.
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).
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.
PMCID: PMC3844668  PMID: 23594745
Hemoglobin A1c; blood glucose; equation model; glycemic control; albumin; hemoglobin; peritoneal dialysis; race
34.  Metabolic Syndrome, Vitamin D Deficiency and Hypoadiponectinemia among Non-Diabetic Patients Early after Kidney Transplantation 
American journal of nephrology  2013;37(5):10.1159/000349930.
Background and Aims
Metabolic syndrome (MetS) is common among kidney transplant patients. We studied the relationship between MetS, vitamin D deficiency/insufficiency and hypoadiponectinemia early post-transplantation and their impact on clinical outcomes.
Seventy-four previously non-diabetic kidney transplant patients were enrolled in a prospective cohort study between February and November 2008. Participants underwent a 2-hours oral glucose tolerance test (OGTT) and had their plasma levels of 25-hydroxyvitamin D (25[OH]D), adiponectin, insulin, intact parathyroid hormone and lipids measured at 11 weeks after transplantation. Clinical events including cardiovascular events, new onset diabetes after transplantation, acute rejection, graft loss and death were recorded during the follow-up to December 2012.
Thirty-four study patients (45.9%) had MetS. Patients with MetS had lower plasma concentrations of 25[OH]D (20.5±7.2 vs. 24.8±11.1 ng/ml, p=0.049) and adiponectin (8.2±4.5 vs. 14.6±8.0 μg/ml, p<0.0001) early on, and higher composite clinical event rate (61.8% vs. 27.5%, p=0.003) during the follow-up. Multivariate analysis showed that the presence of MetS early after transplantation was independently associated with 25[OH]D insufficiency/deficiency (OR 14.0, 95% CI 1.8, 107.5, p=0.011), depressed plasma adiponectin levels (β -6.39, r2 0.195, p<0.0001) and increased risk for clinical events (OR 5.6, 95% CI 1.9, 16.5, p=0.002).
Kidney transplants patients with MetS early after transplantation had lower levels of 25[OH]D and adiponectin, and unfavorable clinical outcomes.
PMCID: PMC3816759  PMID: 23751485
adiponectin; clinical outcomes; kidney transplantation; metabolic syndrome; vitamin D deficiency
35.  Prevalence of pre-ESRD care and associated outcomes among urban, micropolitan, and rural dialysis patients 
American journal of nephrology  2013;37(3):274-280.
Pre-ESRD care associates with improved outcomes among patients receiving dialysis. It is unknown what proportion of US micropolitan and rural dialysis patients receive pre-ESRD care and benefit from such care when compared to urban.
A retrospective cohort study was performed using data from the US Renal Data System. Patients ≥18 years old who initiated dialysis in 2006 and 2007 were classified as rural, micropolitan, or urban and prevalence of pre-ESRD care (early nephrology care >6 months, permanent vascular access, dietary education) was determined using the medical evidence report. The association of pre-ESRD care with dialysis mortality and transplantation was assessed using Cox regression with stratification for geographic residence.
Of 204,463 dialysis patients, 80% were urban, 10.2% were micropolitan, and 9.8% were rural. Overall attainment of pre-ESRD care was poor. After adjustment, there were no significant geographic differences in attainment of early nephrology care or permanent dialysis access. Receiving care reduced all-cause mortality and increased the likelihood of transplantation to a similar degree regardless of geographic residence. Both micropolitan and rural patients received less dietary education (RR 0.80 95% CI 0.76–0.84 and RR 0.85 95% CI 0.80–0.89, respectively).
Among patients who receive dialysis, the prevalence of early nephrology care and permanent dialysis access is poor and does not vary by geographic residence. Micropolitan and rural patients receive less dietary education despite an observed mortality benefit, suggesting that barriers may exist to quality dietary care in more remote locations.
PMCID: PMC3787839  PMID: 23548738
rural; disparity; chronic kidney disease
37.  Low Body Mass Index and Dyslipidemia in Dialysis Patients linked to Elevated Plasma Fibroblast Growth Factor 23 
American journal of nephrology  2013;37(3):183-190.
Fibroblast growth factor 23 (FGF23) has been associated with death in dialysis patients. Since FGF23 shares structural features with FGF19-subfamily members that exert hormonal control of fat mass, we hypothesized that high circulating FGF23 concentrations would be associated with the development of a uremic lipid profile and lower body mass index.
This study was conducted among 654 patients receiving chronic hemodialysis. C-terminal FGF23 concentrations were measured in stored plasma samples. Linear regression was used to examine the cross-sectional associations of plasma FGF23 concentrations with body mass index (BMI), total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG). Cox-proportional hazard models were used to examine the association between FGF23 concentrations and all-cause mortality.
Participants had a mean age of 60 ± 11 years and a median [IQR] FGF23 concentration of 4212 [1411-13816] RU/mL. An increase per SD in log10 FGF23 was associated with lower BMI (β= −1.11; p=0.008), TC (β= −6.46; p=0.02), LDL-C (β= −4.73; p=0.04) and HDL-C (β= −2.14; p=0.03); after adjusting for age, gender, race, cardiovascular risk factors, serum albumin, markers of mineral metabolism, and use of lipid lowering drugs. The association of FGF23 with death was attenuated after adjustment for HDL-C (HR of highest quartile 1.53, 95% CI 1.06-2.20 compared to lowest quartile).
These results indicate that higher plasma FGF23 levels are associated with lower BMI and dyslipidemia in dialysis patients. The association between FGF23 and death may be mediated through unexplored metabolic risk factors unrelated to mineral metabolism.
PMCID: PMC3717381  PMID: 23428834
Hemodialysis; fibroblast growth factor 23; dyslipidemia; body mass index
38.  Impact of ultrasound-guided kidney biopsy simulation on trainee confidence and biopsy outcomes 
American journal of nephrology  2012;36(6):570-574.
To improve procedural skill competence in real-time ultrasound-guided renal biopsy, we have developed an inexpensive simulation tool (a porcine kidney inserted under turkey breast) that mimics biopsy conditions in human patients in terms of kidney size, depth, echogenicity and overall structural characteristics. This study investigated the utility of this simulation tool for improving trainees’ confidence in performing renal biopsy and biopsy-associated bleeding complications.
We have quantitatively assessed the confidence level of renal fellows before and after their initial renal biopsy simulation training. Subsequently, we determined the effect of this simulation training on trainees’ procedural competence by comparing outcomes of clinical renal biopsies performed by fellows that did vs those who did not participate in the simulation training.
We show that the renal biopsy simulation has improved the confidence level of trainees (23.4 pre-simulation to 70.3 post-simulation on a 0–100 scale; p=0.001; eta squared=0.69). The improvement in trainees’ confidence did not vary across their prior experience performing renal biopsies (eta squared=0.23, p=0.060). Additionally, fellows who participated in the simulation training demonstrated improved competence in performing the renal biopsy procedure in patients. Successful retrieval of renal tissue per pass was 94% (vs 73 % in fellows who did not participate in this simulation training; p=0.002) and procedure-related blood loss was reduced as indicated by smaller post-biopsy vs pre-biopsy hematocrit decline (1.18 vs 2.68; p=0.049).
Renal biopsy simulation training may improve trainees’ confidence and reduce the severity of biopsy-associated bleeding complications in patients.
PMCID: PMC3918883  PMID: 23221146
kidney biopsy; training; model; bleeding complications
39.  Healthy Behaviors, Risk Factor Control and Awareness of Chronic Kidney Disease 
American journal of nephrology  2013;37(2):135-143.
The association between chronic kidney disease (CKD) awareness and healthy behaviors is unknown. We examined whether CKD self-recognition is associated with healthy behaviors and achieving risk-reduction targets known to decrease risk of cardiovascular morbidity and CKD progression.
CKD awareness, defined as a “yes” response to “Has a doctor or other health professional ever told you that you had kidney disease?”, was examined among adults with CKD (eGFR < 60 ml/min/1.73 m2) who participated in the REasons for Geographic and Racial Differences in Stroke study. Odds of participation in healthy behaviors (tobacco avoidance, avoidance of regular NSAID use, physical activity) and achievement of risk reduction targets (ACEI/ARB use, systolic blood pressure (SBP) control and glycemic control among those with diabetes) among those aware vs. unaware of their CKD were determined by logistic regression, controlling for socio-demographics, access to care and co-morbid conditions. SBP control was defined as < 130 mmHg (primary definition) or < 140 mmHg (secondary definition).
Of 2,615 participants, only 6% (n=166) were aware of having CKD. Those who were aware had 82% higher odds of tobacco avoidance compared to those unaware [adjusted odds ratio =1.82, 95% CI (1.02–3.24)]. CKD awareness was not associated other healthy behaviors or achievement of risk-reduction targets.
Awareness of CKD was only associated with participation in one healthy behavior and was not associated with achievement of risk-reduction targets. To encourage adoption of healthy behaviors, a better understanding of barriers to participation in CKD-healthy behaviors is needed. Keywords: chronic kidney disease, awareness, behaviors, self-management
PMCID: PMC3649001  PMID: 23392070
Chronic kidney disease; awareness; self-management; behaviors
40.  Role of urea in intestinal barrier dysfunction and disruption of epithelial tight junction in CKD 
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.
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.
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.
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.
PMCID: PMC3686571  PMID: 23258127
Endotoxin; Inflammation; Gastrointestinal pathology; End-stage renal disease; uremia; cardiovascular disease
41.  Relationship of Urine Dopamine with Phosphorus Homeostasis in Humans: The Heart and Soul Study 
American journal of nephrology  2012;35(6):10.1159/000338483.
Urine dopamine (DA) is produced in the proximal tubule and has been found to increase in response to dietary phosphorus intake, and to contribute to greater urinary phosphorus excretion in animal models. Whether urine DA is associated with phosphorus homeostasis in humans is uncertain.
This was a cross-sectional study of 884 outpatients. DA was measured from 24-hour urine collections. We examined cross-sectional associations between urine DA and serum phosphorus, 24-hour urine phosphorus (as an indicator of dietary phosphorus absorption), fractional excretion of phosphorus (FEphos), fibroblast growth factor (FGF)-23, and parathyroid hormone (PTH). Models were adjusted for age, sex, race, eGFR, albuminuria, hypertension, heart failure, tobacco use, body mass index, and diuretic use.
Mean age was 66.6 ± 11 years and mean eGFR was 71 ± 21.3 ml/min/1.73 m2. The mean urine DA was 193 ± 86 µg/day, mean serum phosphorus was 3.6 ± 0.6 mg/dl, mean daily urine phosphorus excretion was 671 ± 312 mg/day, and mean FEphos was 17 ± 9%. In adjusted models, each standard deviation higher DA was associated with 78.4 mg/day higher urine phosphorus and 0.9% lower FEphos (p < 0.05 for both). There was no statistically significant association between urine DA, serum phosphorus, FGF-23 or PTH in adjusted models.
Higher dietary phosphorus absorption is associated with higher urine DA in humans, consistent with animal models. However, higher urine DA is not associated with FGF-23 or PTH, suggesting that known mechanisms of renal tubular handling of phosphorus may not be involved in the renal dopamine-phosphorus regulatory pathway in humans.
PMCID: PMC3873852  PMID: 22572568
Urine dopamine; Phosphorus; Kidney; Proximal tubule
42.  Association between Non-Alcoholic Liver Disease and Chronic Kidney Disease: An Ultrasound Analysis from NHANES 1988–1994 
American journal of nephrology  2012;36(5):466-471.
Background/ Aims
Non-alcoholic fatty liver disease (NAFLD) has been proposed to contribute to chronic kidney disease (CKD) independently of traditional cardiometabolic risk factors. We hypothesized that NAFLD is associated with CKD and that greater severity of NAFLD is associated with higher odds of CKD.
A cross-sectional analysis of 11,469 adults who participated in the National Health and Nutrition Examination Survey 1988–1994. NAFLD was defined by ultrasonographic detection of steatosis in the absence of other liver diseases. CKD was defined as an estimated glomerular filtration rate of ≤60 mL/min/1.73 m2 or the presence of albuminuria in subjects with an estimated glomerular filtration rate of >60 mL/min/1.73 m2.
2,891 (25.4%) patients in the cohort had CKD. The prevalence of NAFLD was higher in individuals with CKD compared to those without CKD (42.2% vs. 34.5%, p<0.0001). NAFLD was associated with CKD in unadjusted logistic regression analysis (odds ratio 1.47, 95% confidence interval 1.29–1.67, p<0.0001). Adjustment for demographics and components of metabolic syndrome attenuated this relationship (odds ratio 1.04, 95% confidence interval 0.88–1.23, p=0.64). Moderate and severe NAFLD on ultrasound were increasingly associated with prevalent CKD in unadjusted analysis but not after adjustment for metabolic syndrome components.
After adjusting for features of metabolic syndrome, ultrasound-diagnosed NAFLD is not associated with prevalent CKD among US adults. Aggressive public health efforts are needed to prevent and treat metabolic syndrome.
PMCID: PMC3563287  PMID: 23128368
chronic kidney disease; nonalcoholic fatty liver disease; NHANES
43.  Low Blood Levels of Long Chain n-3 Polyunsaturated Fatty Acids in U.S. Hemodialysis Patients: Clinical Implications 
American journal of nephrology  2012;36(5):451-458.
Cardioprotective and other clinical benefits of long chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) are inversely related to dietary intake and hence blood content. We therefore investigated, in the first study of its kind, the blood content and distribution of these fatty acids in a large representative population of U.S. hemodialysis patients.
Frozen sera were obtained from 400 individuals who were part of a large, contemporary, representative cohort of U.S. incident hemodialysis patients. LC n-3 PUFA were measured in total serum lipids and in the neutral and polar serum fractions using gas chromatography and solid phase extraction techniques. Mean LC n-3 PUFA levels were compared to levels of other dialysis and non-dialysis populations from published reports.
The study population was qualitatively similar to the overall U.S. hemodialysis population in terms of major clinical characteristics. LC n-3 PUFA were present in the serum polar fraction, with essentially none being detected in the neutral fraction (P<0.0001 for polar versus neutral fractions for all three LC n-3 PUFA). Mean serum LC n-3 PUFA levels (weight %(±SD): total-1.55±0.95, polar-3.99± 1.45) were low compared to non-dialysis and most other non-U.S. hemodialysis cohorts.
While U.S. hemodialysis patients have a blood distribution of LC n-3 PUFA that is similar to that in the general population, blood content is among the lowest recorded in the medical literature. This has implications for renal dietary recommendations and makes U.S. patients an ideal group in which to test the clinical effects of LC n-3 PUFA supplementation.
PMCID: PMC3784309  PMID: 23128302
omega-3; fatty acids; hemodialysis; cardiovascular; nutrition
44.  Uremic plasma impairs barrier function and depletes the tight junction protein constituents of intestinal epithelium 
American journal of nephrology  2012;36(5):438-443.
Back ground
CKD causes intestinal barrier dysfunction which by allowing influx of endotoxin and other noxious products contributes to the CKD-associated systemic inflammation and uremic toxicity. We have recently shown that intestinal barrier dysfunction in CKD animals is due to degradation of trans-cellular [claudin-1 and occludin] and intra-cellular [ZO1] constituents of epithelial tight junction (TJ). This study determined whether CKD-associated disruption of TJ is mediated by retained uremic toxins/metabolites and if so whether they are removed by hemodialysis.
The TJ-forming human enterocytes (T84 cells) were seeded on the Transwell plates and utilized when trans-epithelial electrical resistance (TER) exceeded 1000 mΩ/cm2 to ensure full polarization and TJ formation. The cells were then incubated for 24 hr in media containing 10% pre- or post-hemodialysis plasma from ESRD patients or healthy individuals. TER was then measured and cells were processed for Western blot and immunohistological analyses.
Compared with the control plasma, incubation in media containing pre-dialysis plasma from ESRD patients resulted in a marked drop in TER pointing to increased epithelial permeability. This was accompanied by significant reductions in cluadin-1 (85%), occludin (15%), and ZO1 (70%) abundance. The severity of TJ damage and dysfunction was significantly less in cells exposed to the post-dialysis than per-dialysis plasma. These findings point to the presence of as-yet unidentified product(s) in the uremic plasma capable of depleting epithelial TJ.
Exposure to uremic milieu damages the intestinal epithelial TJ and impairs its barrier function, events which are mediated by agents which are partially removed by hemodialysis.
PMCID: PMC3725306  PMID: 23128155
Tight junction; inflammation; hemodialysis; ESRD; CKD
45.  Association between kidney function and telomere length: the Heart and Soul Study 
American journal of nephrology  2012;36(5):405-411.
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.
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.
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.
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.
PMCID: PMC3552638  PMID: 23108000
kidney; CKD; telomere
46.  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.
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).
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.
PMCID: PMC3538165  PMID: 23107930
carotid intima media thickness; coronary artery calcification; kidney; plaque
47.  Preservation of blood pressure stability with hypertonic mannitol during hemodialysis initiation 
American journal of nephrology  2012;36(2):168-174.
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.
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.
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).
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.
PMCID: PMC3779621  PMID: 22846598
hemodialysis; intra-dialytic hypotension; mannitol; osmolality
48.  The Association of Plasma Fluorescent Oxidation Products and Chronic Kidney Disease: A Case-Control Study 
American journal of nephrology  2012;36(4):297-304.
Plasma fluorescent oxidation products (FLOP) constitute a stable and easily-measured biomarker of cumulative oxidative stress. However, its association with chronic kidney disease (CKD) has not been studied.
We examined the association of FLOP and CKD in 201 CKD patients and 201 controls without CKD from the community. CKD was defined as estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 or presence of albuminuria.
Adjusted median (interquartile range) of FLOP was significantly higher in patients with CKD than in controls [FLOP1 (lipid oxidation products): 215.2 fluorescent intensity (FI)/mL (181.3, 268.7) vs. 156.6 FI/mL (139.6, 177.3), p<0.0001; FLOP2 (DNA oxidation products): 534.8 FI/mL (379.3, 842.4) vs. 269.9 FI/mL (232.4, 410.5), p<0.0001; FLOP3 (protein and phospholipids oxidation products): 51.4 FI/mL (44.4, 66.0) vs. 45.2 FI/mL (38.3, 51.7), p=0.002]. Compared with those with a FLOP level below the 75th percentile, participants with a FLOP level above the 75th percentile had an increased odds of CKD after adjustment for covariables [FLOP1: odds ratio (OR), 13.1, 95% confidence interval (CI), 6.2, 27.6; FLOP2: OR, 5.7, 95% CI, 2.9, 11.1; FLOP3: OR, 2.4, 95% CI, 1.2, 4.7]. Levels of FLOP1, FLOP2, and FLOP3 were related to eGFR (all p-values <0.0001) and log-transformed urine albumin (all p-values <0.005) in multivariable adjusted linear regression models.
These data indicate that elevated FLOP level is associated with CKD status and severity. Future studies are warranted to elucidate its role in the development and progression of CKD.
PMCID: PMC3557790  PMID: 22986784
albuminuria; biological markers; case-control study; glomerular filtration rate; kidney diseases; oxidative stress
49.  Relevance of the ACTN4 gene in African Americans with non-diabetic ESRD 
American journal of nephrology  2012;36(3):252-260.
African Americans (AAs) are predisposed to non-diabetic (non-DM) end-stage renal disease (ESRD) and studies have shown a genetic component to this risk. Rare mutations in ACTN4 (α-actinin-4) an actin binding protein expressed in podocytes cause familial focal segmental glomerulosclerosis.
We assessed the contribution of coding variants in ACTN4 to non-DM ESRD risk in AAs. Nineteen exons, 2800 bases of the promoter and 392 bases of the 3’ untranslated region of ACTN4 were sequenced in 96 AA non-DM ESRD cases and 96 non-nephropathy controls (384 chromosomes). Sixty-seven single nucleotide polymorphisms (SNPs) including 51 novel SNPs were identified. The SNPs comprised 33 intronic, 21 promoter, 12 exonic, and 1 3’ variant. Sixty-two of the SNPs were genotyped in 296 AA non-DM ESRD cases and 358 non-nephropathy controls.
One SNP, rs10404257, was associated with non-DM ESRD (p<1.0E-4, odds ratio (OR)=0.76, confidence interval (CI)=0.59–0.98; additive model). Forty-seven SNPs had minor allele frequencies less than 5%. These SNPs were segregated into risk and protective SNPs and each category was collapsed into a single marker, designated by the presence or absence of any rare allele. The presence of any rare allele at a risk SNP was significantly associated with non-DM ESRD (p = 0.001, dominant model). The SNPs with the strongest evidence for association (n = 20) were genotyped in an independent set of 467 non-DM ESRD cases and 279 controls. Although, rs10404257 was not associated in this replication sample, when the samples were combined rs10404257 was modestly associated (p=0.032, OR=0.78, CI=0.63–0.98; dominant model). SNPs were tested for interaction with markers in the APOL1 gene, previously associated with non-DM ESRD in AAs and rs10404257 was modestly associated (p = 0.0261, additive model).
This detailed evaluation of ACTN4 variation revealed limited evidence of association with non-DM ESRD in AAs.
PMCID: PMC3510331  PMID: 22965004
ACTN4; non-diabetic ESRD; FSGS; kidney; hypertensive nephrosclerosis; African Americans
50.  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.
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.
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.
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.
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.
PMCID: PMC3510352  PMID: 22964976
sex difference; gender difference; diabetic kidney disease

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