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26.  Current Concepts in the Diagnosis and Classification of Renal Dysfunction in Cirrhosis 
American journal of nephrology  2013;38(4):345-354.
Background
Renal dysfunction is one of the most common complications of cirrhosis with high morbidity and mortality.
Summary
In subjects with cirrhosis, renal dysfunction can present either as a direct consequence of cirrhosis (e.g. hepatorenal syndrome Type I and Type II) or secondary to etiologies other than cirrhosis (chronic kidney disease due to diabetic nephropathy, prerenal azotemia). Or, patients with cirrhosis may have renal dysfunction resulting directly from cirrhosis; and an underlying chronic kidney disease.
Key Messages
Given the challenges in the differential diagnosis of renal dysfunction and insufficient accuracy of serum creatinine and creatinine-based glomerular filtration rate estimating equations in cirrhosis, there is an urgent need for more accurate biomarkers of renal dysfunction in this population. This review will discuss novel concepts for the diagnosis and classification of renal dysfunction in cirrhosis to overcome at least some of the diagnostic and therapeutic challenges. Additionally, a new classification will be proposed for renal dysfunction in cirrhosis.
doi:10.1159/000355540
PMCID: PMC4072495  PMID: 24107793
Hepatorenal Syndrome; Cirrhosis; Creatinine; Cystatin C; Renal Dysfunction
27.  Physical Performance and Frailty in Chronic Kidney Disease 
American journal of nephrology  2013;38(4):307-315.
Background
Poor physical performance and frailty are associated with elevated risks of death and disability. Chronic kidney disease (CKD) is also strongly associated with these outcomes. The risks of poor physical performance and frailty among CKD patients, however, are not well established.
Methods
We measured the Short Physical Performance Battery (SPPB, a summary test of gait speed, chair-raises and balance; range 0–12) and the five elements of frailty among 1111 Chronic Renal Insufficiency Cohort participants. Adjusting for demographics and multiple comorbidities, we fit a linear regression model for the outcome of SPPB score and an ordinal logistic regression model for frailty status.
Results
Median (interquartile range [IQR]) age was 65 (57–71) years, median estimated glomerular filtration rate (eGFR) for non-dialysis patients was 49 (36–62) ml/min/1.73m2, and median SPPB score was 9 (7–10). Seven percent of participants were frail and 43% were pre-frail. Compared with the SPPB score for eGFR >60 ml/min/1.73m2, the SPPB was 0.51 points lower for eGFR 30 – 59; 0.61 points lower for eGFR 15 – 29; and 1.75 points lower for eGFR <15; (p<0.01 for all comparisons). eGFR 30 – 59 (OR 1.45; p=0.024), eGFR 15 – 29 (OR 2.02; p=0.002) and eGFR <15 (OR 4.83, p<0.001) were associated with worse frailty status compared with eGFR >60 ml/min/1.73m2.
Conclusions
CKD severity was associated with poor physical performance and frailty in a graded fashion. Future trials should determine if outcomes for CKD patients with frailty and poor physical performance are improved by targeted interventions.
doi:10.1159/000355568
PMCID: PMC4019506  PMID: 24107579
Physical performance; frailty; chronic kidney disease
28.  Differential diagnosis of glomerular disease: a systematic and inclusive approach 
American journal of nephrology  2013;38(3):10.1159/000354390.
Background
Glomerular disease is a complex and evolving topic. In evaluating a specific case it is not unusual for the clinician to ask: Am I missing something? Should I biopsy? When? Should I treat first, then biopsy? This work, which is both evidence based and experience based, is intended to address each of these concerns, and many other issues relevant to the differential diagnosis of glomerular disease.
Summary
The central approach is the use of diagnostic algorithms that are based on quantitative measures routinely obtained early in the course of the diagnostic evaluation. The algorithms are designed to be easy to navigate, systematic, and inclusive. Also provided is a detailed and prioritized list of recommended diagnostic testing, and the rationale for each test.
Key message
This work is intended to facilitate accurate diagnosis in the individual patient presenting with evidence of glomerular disease.
doi:10.1159/000354390
PMCID: PMC3842189  PMID: 24052039
glomerular disease; proteinuria; glomerulonephritis
29.  Endothelial dysfunction occurs prior to clinical evidence of Polycystic Kidney Disease 
American journal of nephrology  2013;38(3):10.1159/000354236.
Objective
Polycystic kidney disease (PKD), a monogenic disease with an autosomal dominant or an autosomal recessive form of inheritance (ARPKD), is the most common genetic cause of renal dysfunction and end stage renal failure. In addition to the development of cysts, the autosomal form of PKD is associated with vascular endothelial dysfunction, a marker of vascular disease. Whether vascular endothelial dysfunction is also present in ARPKD, and the relationship with renal dysfunction remains to be determined.
Methods
ARPKD rats (PCK model) and controls were studied at 6 and 10 weeks of age, and mean arterial pressure (MAP) and renal function were measured. Aortic endothelial function was assessed using organ chamber techniques. Aortic endothelial cells (ECs) were isolated, characterized and their function studied.
Results
Compared to controls, ARPKD animals had a decrease in the vasorelaxation to endothelium-dependent vasodilators, even prior to changes in MAP or renal function. The abnormal vasoreactivity was corrected with L-arginine (precursor to nitric oxide), while the expression of endothelial nitric oxide synthase (eNOS) was unchanged. Furthermore, isolated ECs from 6 week-old ARPKD animals showed increased oxidative stress, with preserved eNOS expression and abnormal patterns of migration and angiogenic capacity (measured by the scratch and tube formation assays, respectively).
Conclusion
ARPKD leads to impaired aortic vascular function and ECs at an early stage, which can have significant functional consequences, potentially representing a novel therapeutic target in this disease.
doi:10.1159/000354236
PMCID: PMC3835344  PMID: 24008943
polycystic kidney disease; cardiovascular; kidney; endothelial dysfunction; acetylcholine
30.  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
31.  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
32.  Assessment of printed patient-educational materials for chronic kidney disease 
American journal of nephrology  2013;38(3):184-194.
Background
Awareness of chronic kidney disease (CKD) is suboptimal among patients with CKD, perhaps due to poor readability of patient education materials (PEMs). We reviewed the suitability and readability of common PEMs that focused on 5 content areas: basics of CKD, risk factors for CKD development, risk factors for CKD progression, complications of CKD and self-management strategies to improve kidney health.
Methods
Three reviewers (nephrologist, primary care physician, patient) used the Suitability Assessment of Materials to rate PEMs on message content/stimulation of learning, typography, visuals and layout and determined literacy level. Mean ratings were calculated for each PEM by content area and overall (Superior=70–100; Adequate=40–69; Inadequate=<40). Linear regression was used to determine the impact of literacy level on mean rating.
Results
We reviewed 69 PEMs from 19 organizations, divided into 113 content area sections. Most (79%) PEM sections were “Adequate” (mean rating, 58.3%). Inclusion of patient-centered content and opportunities for patient interaction were associated with “Superior” ratings. Mean ratings (SD) were similar across content areas: basics of CKD, 58.9% [9.1]; risk factors for CKD development, 57.0% [12.3]; risk factors for CKD progression, 58.5% [12.0]; CKD complications, 62.3% [15.7] and self-management strategies, 62.2% [12.3]. ≤ 6th grade literacy level (vs >6th grade) was associated with an 11.7 point higher mean rating.
Conclusion
Most PEMs for kidney disease were adequate. Outstanding PEMs shared characteristics of patient centeredness, a low literacy level, and patient interaction. Providers should be aware of strengths and limitations of PEMs when educating their patients about CKD.
doi:10.1159/000354314
PMCID: PMC3804301  PMID: 23970127
chronic kidney disease; health literacy; patient education materials
33.  Effects of Phosphate Binder Therapy on Vascular Stiffness in Early Stage Chronic Kidney Disease 
American journal of nephrology  2013;38(2):10.1159/000353569.
Background/Aims
Cardiovascular disease (CVD) is increased in chronic kidney disease (CKD), and contributed to by the CKD-mineral bone disorder (CKD-MBD). The CKD-MBD begins in early CKD and its vascular manifestations begin with vascular stiffness proceeding to increased carotid artery intima-media thickness (cIMT) and vascular calcification (VC). Phosphorus is associated with this progression and is considered a CVD risk factor in CKD. We hypothesized that modifying phosphorus balance with lanthanum carbonate (LaCO3) in early CKD would not produce hypophosphatemia and may affect vascular manifestations of the CKD-MBD.
Methods
We randomized 38 subjects with normophosphatemic stage 3 CKD to a fixed dose of LaCO3 or matching placebo without adjusting dietary phosphorus in a 12-month randomized, double-blind, pilot and feasibility study. The primary outcome was the change in serum phosphorus. Secondary outcomes were changes in measures of phosphate homeostasis and vascular stiffness assessed by carotid-femoral pulse wave velocity (PWV), cIMT and VC over 12 months.
Results
There were no statistically significant differences between LaCO3 and placebo with respect to the change in serum phosphorus, urinary phosphorus, tubular reabsorption of phosphorus, PWV, cIMT, or VC. Biomarkers of the early CKD-MBD such as plasma fibroblast growth factor-23 (FGF23), Dickkopf-related protein 1 (DKK1), and sclerostin were increased 2–3-fold at baseline but were not affected by LaCO3.
Conclusion
12 months of LaCO3 had no effect on serum phosphorus and did not alter phosphate homeostasis, PWV, cIMT, VC, or biomarkers of the CKD-MBD.
doi:10.1159/000353569
PMCID: PMC3874122  PMID: 23941761
Cardiovascular disease; chronic kidney disease; phosphate binders; vascular calcification; randomized controlled trials
34.  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
35.  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
36.  FATTY ACIDS AND OTHER RISK FACTORS FOR SUDDEN CARDIAC DEATH IN PATIENTS STARTING HEMODIALYSIS 
American journal of nephrology  2013;38(1):10.1159/000351764.
Background
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.
Design
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.
Results
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).
Conclusions
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.
doi:10.1159/000351764
PMCID: PMC3856432  PMID: 23816975
omega-3; fatty acids; sudden cardiac death; hemodialysis; incident; risk factors; nutrition; cardiovascular
37.  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
38.  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.
Background/Aims
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).
Methods
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).
Results
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).
Conclusions
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.
doi:10.1159/000351178
PMCID: PMC3919025  PMID: 23689685
Chronic Kidney Disease; Dietary sodium intake; Dietary potassium intake
39.  Microalbuminuria in HIV Disease 
American journal of nephrology  2013;37(5):10.1159/000350384.
Background/Aims
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1159/000350384
PMCID: PMC3809894  PMID: 23615312
HIV infection; microalbuminuria; urinary albumin-creatinine ratio
40.  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
41.  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
42.  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.
Methods
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.
Results
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).
Conclusion
Kidney transplants patients with MetS early after transplantation had lower levels of 25[OH]D and adiponectin, and unfavorable clinical outcomes.
doi:10.1159/000349930
PMCID: PMC3816759  PMID: 23751485
adiponectin; clinical outcomes; kidney transplantation; metabolic syndrome; vitamin D deficiency
43.  Prevalence of pre-ESRD care and associated outcomes among urban, micropolitan, and rural dialysis patients 
American journal of nephrology  2013;37(3):274-280.
Background/aims
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1159/000348377
PMCID: PMC3787839  PMID: 23548738
rural; disparity; chronic kidney disease
45.  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.
Background
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.
Methods
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.
Results
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).
Conclusion
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.
doi:10.1159/000346941
PMCID: PMC3717381  PMID: 23428834
Hemodialysis; fibroblast growth factor 23; dyslipidemia; body mass index
46.  Impact of ultrasound-guided kidney biopsy simulation on trainee confidence and biopsy outcomes 
American journal of nephrology  2012;36(6):570-574.
Background/Aims
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.
Methods
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.
Resuts
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).
Conclusion
Renal biopsy simulation training may improve trainees’ confidence and reduce the severity of biopsy-associated bleeding complications in patients.
doi:10.1159/000345305
PMCID: PMC3918883  PMID: 23221146
kidney biopsy; training; model; bleeding complications
47.  Healthy Behaviors, Risk Factor Control and Awareness of Chronic Kidney Disease 
American journal of nephrology  2013;37(2):135-143.
Background/Aims
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.
Methods
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).
Results
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.
Conclusions
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
doi:10.1159/000346712
PMCID: PMC3649001  PMID: 23392070
Chronic kidney disease; awareness; self-management; behaviors
48.  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
49.  Relationship of Urine Dopamine with Phosphorus Homeostasis in Humans: The Heart and Soul Study 
American journal of nephrology  2012;35(6):10.1159/000338483.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1159/000338483
PMCID: PMC3873852  PMID: 22572568
Urine dopamine; Phosphorus; Kidney; Proximal tubule
50.  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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1159/000343885
PMCID: PMC3563287  PMID: 23128368
chronic kidney disease; nonalcoholic fatty liver disease; NHANES

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